'Positive biology' as a new paradigm for the medical sciences. Focusing on people who live long, happy, healthy lives might hold the key to improving human well-being

The nearly exclusive focus on understanding and treating chronic disease might not be the most efficient way to improve public health, especially as an effective alternative strategy exists.On 27 April 2009, during a speech at the National Academy of Sciences, US President Barack Obama pledged to invest more than 3% of US GDP in scientific research and development—the amount represented the largest ever investment in research and innovation. However, even a financial investment of such magnitude does not ensure that science is ''well-ordered'' [1], in the sense that the scientific research that is prioritized aspires to address the most significant challenges and problems for humanity.Among the many issues facing society that research must address, improving human health and tackling disease rank high, if not first, on the agenda. Accordingly, a huge fraction of research funding is spent on basic and applied research to further our understanding of the causes of disease and to find new cures and therapies. But is this focus on pathology the most efficient way to conduct research with the aim to improve human health and well-being?…a huge fraction of research funding is spent on basic and applied research to further our understanding of the causes of disease and to find new cures and therapiesMost of today''s medical research could be called ''negative biology''. It is conducted in an intellectual framework that presumes that the most important question to answer is: what causes pathology? Disease is its central focus and this explains why medical research and research funding is mainly concerned with trying to understand, prevent and treat specific diseases. The design of the US National Institutes of Health, which is largely composed of individual institutes dedicated to specific diseases such as cancer, mental illness or infectious diseases, reflects this prevalence of pathology-oriented negative biology.Positive biology, by contrast, focuses on a different set of questions and priorities. Rather than making pathology and disease the central focus of intellectual efforts and financial investments, positive biology seeks to understand positive phenotypes: why do some individuals live more than a century without ever suffering from the chronic diseases that afflict most humans much earlier in their lives? Why are some individuals more happy, optimistic, talented, or have a better memory than most people? The paradigm of positive biology is based on the insight that the process of evolution by natural selection does not create a perfect organism in terms of life expectancy, resistance to disease or other abilities. Observations of exceptional longevity or superior cognition therefore present fascinating puzzles for positive biology: which biological mechanisms would explain these exemplars of health and well-being? The goal of understanding positive phenotypes is that such knowledge might lead to new interventions that generally improve human well-being. This might be achieved by modulating the rate of ageing or by increasing opportunities for play and joy at all stages of the human lifespan, or by developing pharmaceuticals that safely enhance cognition or positive emotions, and so on.The goal of understanding positive phenotypes is that such knowledge might lead to new interventions that generally improve human well-beingThis is distinct from negative biology, which focuses on the proximate causes of specific diseases, rather than on the evolutionary causes of positive phenotypes. It presumes that health, survival and happiness are the default states and aims to explain the deviations: why do we develop cancer? Why do we suffer from depression? Why do we develop hypertension? Negative biology therefore faces the laudable but insurmountable task of trying to prevent or cure all disease. This is a costly and ultimately futile endeavour. Eliminating all types of cancer would increase life expectancy in the USA by approximately only three years [2]. Even eliminating cancer as a cause of death would not prevent any of the other chronic diseases of ageing—cardiovascular disease, Alzheimer and Parkinson disease, diabetes and so on—from afflicting the elderly. Moreover, the more than 40 years of ''war against cancer'' has not defeated a single type of cancer: we still have a long way to go before we can realistically expect to reap the three-year increase in life expectancy that eliminating all cancers could yield.In fact, negative biology has not yet developed a single cure for any one of the hundreds of chronic diseases that afflict millions of people living today. Of course, it has made significant advances to help prevent and treat chronic disease, but the fixation on pathology has meant that other potential avenues for research have been neglected.Indeed, a better understanding of exemplars of health and happiness—the goal of positive biology—could create more benefits for humans more quickly and more easily. A drug that would safely mimic the effects of caloric restriction, for instance, might delay, simultaneously, most diseases and afflictions of ageing. It would generate a much greater health dividend for ageing populations than defeating any one specific disease of ageing because slowing down the rate of ageing by seven years would reduce the age-specific risk of death, frailty and disability by about half at every age [3].Scientists are already making good progress on the project of positive biology, even if the intellectual framework is not yet clearly defined and their topics are rather piecemeal. Richard Miller, for example, a professor of pathology at Michigan University, USA, studies the genetics of ageing in mice and participates in the National Institute of Aging''s multi-institutional programme that evaluates the effects of drugs and nutriceuticals on the ageing process in mice. David Sinclair from Harvard University, USA, and others found that the plant compound resveratrol, which is found in the skin of grapes, can modulate the ageing process. Nir Barzilai and colleagues at the Albert Einstein School of Medicine in New York, USA, have conducted genetic research on more than 500 healthy elderly people between the ages of 95 and 112 years. Michael Rose from the University of California, Irvine, USA, has quadrupled the lifespan of fruit flies by delaying the age of reproduction. Finally, the biologist Cynthia Kenyon demonstrated that in Caenorhabditis elegans, a single gene can control the ageing process. Any of these research projects could eventually lead to the development of a new drug that retards the ageing process and diminishes the onslaught of chronic diseases that typically afflict humans after their sixth decade of life.Similarly, a lot of pioneering work is being undertaken in the burgeoning field of ''positive psychology''. Rather than studying why people suffer from mental illnesses such as depression, schizophrenia or ADHD (attention deficit hyperactivity disorder), positive psychology is primarily interested in how to improve the happiness of the ''average'' person. Martin Seligman, a psychologist at the University of Pennsylvania, USA, and a pioneer in the field of positive psychology, distinguishes different kinds and levels of happiness [4]. Hedonists who pursue immediate rewards such as the pleasure of buying something or receiving a compliment seek momentary happiness or what Seligman calls ''the pleasant life''. But these pleasures fade quickly and do not leave a lasting impact on subjective well-being. Enduring happiness, by contrast, is realized when we lead a meaningful life. After years spent studying what makes people happy, Seligman contends that it is rooted in attachment to something larger, and the larger the entity to which you attach yourself, the more meaning your life has [4].Eliminating all types of cancer would increase life expectancy in the USA by approximately only three yearsThis is clearly illustrated by the role of wealth. People often assume that being richer will mean being happier, yet surveys in many countries indicate that global levels of life satisfaction or happiness have not changed much during the past four decades despite large increases in real income per capita [5]. Most disposable income is spent on consumer goods that do little to actually enhance our well-being.In a recent study of the daily behaviour of happy people, researchers used an electronically activated recorder to record, and then later classify, participants'' daily conversations with others as either ''small talk'', that is banal conversations, and ''substantive talk'', where meaningful information was exchanged. They found that higher well-being was associated with less small talk and more substantive conversations [6]. While such a study does not establish the truth of Socrates'' famous claim that “the unexamined life is not worth living”, it does suggest that our need to feel attached to something larger is important to our happiness and well-being. This hypothesis is supported by recent studies on how people spend their money. Researchers from the University of British Columbia and Harvard Business School found that when individuals spend more money on prosocial goals, such as charity, they actually experience greater happiness than when they spend money on consumer products for themselves [7]. Similarly, the psychologist Barbara Fredrickson''s research on positive emotions—joy, serenity and gratitude—suggests that these expand cognition and behavioural tendencies [8].Finally, research on exemplars of resilience, that is, the ability of some people to cope and manage with tragic and traumatic events, could lead to the development of drugs that would increase people''s resilience. Avshalom Caspi and colleagues found that individuals with one or two copies of the short allele of the promoter of the 5-HTT serotonin receptor experience more depressive symptoms, diagnosable depression and suicidal thoughts in response to stressful events compared with individuals who are homozygous for the long allele [9].Cognitive functioning is another central topic of positive biology. What are the genetic and environmental determinants of high IQ, exceptional memory or social intelligence? Barbara Sahakian and colleagues found that the analeptic drug modafinil significantly enhanced performance tests of digit span, visual pattern recognition memory, spatial planning and stop-signal reaction time in healthy volunteers [10]. These findings of positive biology will eventually give us a better understanding of our human nature than the very limited focus on disease and pathology of negative biology and might then lead to new interventions, environments and attitudes that improve human well-being and happiness.Negative biology dominates medical research, from the questions research scientists tackle to the education of physicians and government regulation of health interventions. The dominance of this approach to the medical sciences presumes that the most important questions concern the causes of pathology rather than the causes of exemplar health and happiness. Positive biology takes a different approach: it does not limit the moral duty to apply knowledge and technology to improve human welfare to only treating specific diseases or impairments. Rather, it works under the assumption that if knowledge and research can improve people''s lives, there is a moral duty to advance that knowledge and promote well-being. Nor is positive biology predicated on a sharp distinction between therapy and enhancement. Instead, as the bioethicist John Harris has argued, “the overwhelming moral imperative for both therapy and enhancement is to prevent harm and confer benefit. Bathed in that moral light, it is unimportant whether the protection or benefit conferred is classified as enhancement or improvement, protection or therapy” [11].Generally, the medical system as a whole could be much more efficient if it concentrated its efforts on making people healthier and happier in the first place instead of its current focus on understanding and treating disease. Advancing the paradigm of positive biology should therefore help the medical sciences transcend the limited perspectives and aspirations of negative biology. Such a paradigm could help the world''s population to reap the benefits that new knowledge and technologies can offer in terms of making people healthier and happier. Societies and individuals already seek to achieve these goals: we educate our children to eat healthily and exercise and to develop their social goals to find fulfilment in life. The paradigm of positive biology simply encourages us to make use of the full range of options to realize these goals.…the medical system as a whole could be much more efficient if it concentrated its efforts on making people healthier and happier in the first place…In conclusion, positive biology is not contrary to the goals and aspirations of negative biology. Indeed the two paradigms are often complementary. For example, understanding why some high-risk individuals, such as sex workers, seem to have an intrinsic resistance to HIV-1 might spur the development of an HIV vaccine [12]. Similarly, understanding human brains with exceptional cognitive functioning might lead to new avenues for developing drugs and therapies against severe cognitive impairment. Understanding exemplars of health could create real benefits for those who are more vulnerable to disease and disability.     

Brief intervention to prevent hazardous drinking in young people aged 14--15 in a high school setting (SIPS JR-HIGH): study protocol for a randomized controlled trial

ABSTRACT: BACKGROUND: Whilst the overall proportion of young people drinking alcohol in the United Kingdom has decreased in recent years, those who do drink appear to drink a larger amount, and more frequently. Early and heavy drinking by younger adolescents is a significant public health problem linked to intellectual impairment, increased risk of injuries, mental health issues, unprotected or regretted sexual experience, violence, and sometimes accidental death, which leads to high social and economic costs. This feasibility pilot trial aims to explore the feasibility of delivering brief alcohol intervention in a school setting with adolescents aged 14 and 15 and to examine the acceptability of study measures to school staff, young people and parents.Methods and designSeven schools across one geographical area in the North East of England will be recruited. Schools will be randomly allocated to one of three conditions: provision of an advice leaflet (control condition, n = 2 schools); a 30-minute brief interactive session, which combines structured advice and motivational interviewing techniques delivered by the school learning mentor (level 1 condition, n = 2 schools); and a 60-minute session involving family members delivered by the school learning mentor (level 2 condition, n = 3 schools). Participants will be year 10 school pupils (aged 14 and 15) who screen positively on a single alcohol screening question and who consent to take part in the trial. Year 10 pupils in all seven schools will be followed up at 6 and 12 months. Secondary outcome measures include the ten-question Alcohol-Use Disorders Identification Test. The EQ-5D-Y and a modified short service use questionnaire will inform the health and social resource costs for any future economic evaluation.Young people recruited into the trial will also complete a 28-day timeline follow back questionnaire at 12-month follow-up. A qualitative evaluation (with young people, school staff, learning mentors, and parents) will examine facilitators and barriers to the use of screening and brief intervention approaches in the school setting in this age group.Trial registrationTrial reference number ISRCTN07073105.     

Bioengineered nisin derivatives with enhanced activity in complex matrices

Nisin A is the best known and most extensively characterized lantibiotic. As it is ribosomally synthesized, bioengineering‐based strategies can be used to generate variants. We have previously demonstrated that bioengineering of the hinge region of nisin A can result in the generation of variants with enhanced anti‐microbial activity against Gram‐positive pathogens. Here we created a larger bank of hinge variant producers and screened for producers that exhibit enhanced bioactivity as assessed by agar‐based assays against a selection of target strains. Further analysis of 12 ‘lead’ variants reveals that in many cases enhanced bioactivity is not attributable to enhanced specific activity but is instead as a consequence of an enhanced ability to diffuse through complex polymers. In the case of two variants, which contain the residues SVA and NAK, respectively, within the hinge region, we demonstrate that this enhanced trait enables the peptides to dramatically outperform nisin A with respect to controlling Listeria monocytogenes in commercially produced chocolate milk that contains carrageenan as a stabilizer.     

Visuospatial information in the retinotectal system of xenopus before correct image formation by the developing eye

The retinotectal pathway of Xenopus laevis is a well-established experimental model for studying activity-dependent processes during visual system development. Such processes can be guided by stimulus-evoked activity patterns, which depend on the refractive characteristics of the eye. Previous work has shown that many animals are hyperopic at early developmental stages due to immature refractive properties. Whether this is also the case for Xenopus laevis is unknown. Here, we measure the focal length of the lens and the size of the eye of embryos at different stages and find that Xenopus laevis exhibits a similar shift from hyperopia to emmetropia. At early stages, immediately after innervation of the tectum by the optic nerve, Xenopus embryos are hyperopic. Soon afterwards the focal length of the lens decreases and the eye converges to a state of emmetropia. Despite being hyperopic we find that some visuospatial information is available to the young circuit. Calculations based on the optical properties of the eye show that even when the animals are hyperopic the blurred retinal image provides a crude spatial resolution. Furthermore, using whole-cell recordings in the optic tectum combined with visual stimulation through the intact eye, we show that tectal neurons in hyperopic embryos have spatially restricted glutamatergic receptive fields. Our data demonstrate that Xenopus laevis eyes undergo a process of developmental emmetropization, and suggest that despite an initial stage of suboptimal image formation there is potentially enough information to guide activity-dependent refinements of the retinotectal pathway from the onset of vision.     

Experimental and computational analyses of the energetic basis for dual recognition of immunity proteins by colicin endonucleases

Colicin endonucleases (DNases) are bound and inactivated by immunity (Im) proteins. Im proteins are broadly cross-reactive yet specific inhibitors binding cognate and non-cognate DNases with K_d values that vary between 10^− 4 and 10^− 14 M, characteristics that are explained by a ‘dual-recognition’ mechanism. In this work, we addressed for the first time the energetics of Im protein recognition by colicin DNases through a combination of E9 DNase alanine scanning and double-mutant cycles (DMCs) coupled with kinetic and calorimetric analyses of cognate Im9 and non-cognate Im2 binding, as well as computational analysis of alanine scanning and DMC data. We show that differential ΔΔGs observed for four E9 DNase residues cumulatively distinguish cognate Im9 association from non-cognate Im2 association. E9 DNase Phe86 is the primary specificity hotspot residue in the centre of the interface, which is coordinated by conserved and variable hotspot residues of the cognate Im protein. Experimental DMC analysis reveals that only modest coupling energies to Im9 residues are observed, in agreement with calculated DMCs using the program ROSETTA and consistent with the largely hydrophobic nature of E9 DNase-Im9 specificity contacts. Computed values for the 12 E9 DNase alanine mutants showed reasonable agreement with experimental ΔΔG data, particularly for interactions not mediated by interfacial water molecules. ΔΔG predictions for residues that contact buried water molecules calculated using solvated rotamer models met with mixed success; however, we were able to predict with a high degree of accuracy the location and energetic contribution of one such contact. Our study highlights how colicin DNases are able to utilise both conserved and variable amino acids to distinguish cognate from non-cognate Im proteins, with the energetic contributions of the conserved residues modulated by neighbouring specificity sites.     

Low temperature effects on leaf physiology and survivorship in the C3 and C4 subspecies of Alloteropsis semialata

The species richness of C(4) grasses is strongly correlated with temperature, with C(4) species dominating subtropical ecosystems and C(3) types predominating in cooler climates. Here, the effects of low temperatures on C(4) and C(3) grasses are compared, controlling for phylogenetic effects by using Alloteropsis semialata, a unique species with C(4) and C(3) subspecies. Controlled environment and common garden experiments tested the hypotheses that: (i) photosynthesis and growth are greater in the C(4) than the C(3) subspecies at high temperatures, but this advantage is reversed below 20 degrees C; and (ii) chilling-induced photoinhibition and light-mediated freezing injury of leaves occur at higher temperature thresholds in the C(4) than the C(3) plants. Measurements of leaf growth and photosynthesis showed the expected advantages of the C(4) pathway over the C(3) type at high temperatures. These declined with temperature, but were not completely lost until 15 degrees C, and there was no evidence of a reversal to give a C(3) advantage. Chronic chilling (5-15 degrees C) or acute freezing events induced a comparable degree of photodamage in illuminated leaves of both subspecies. Similarly, freezing caused high rates of mortality in the unhardened leaves of both subtypes. However, a 2-week chilling treatment prior to these freezing events halved injury in the C(3) but not the C(4) subspecies, suggesting that C(4) leaves lacked the capacity for cold acclimation. These results therefore suggest that C(3) members of this subtropical species may gain an advantage over their C(4) counterparts at low temperatures via protection from freezing injury rather than higher photosynthetic rates.     

Consequences of C4 photosynthesis for the partitioning of growth: a test using C3 and C4 subspecies of Alloteropsis semialata under nitrogen-limitation

C(4) plants dominate the world's subtropical grasslands, but investigations of their ecology typically focus on climatic variation, ignoring correlated changes in soil nutrient concentration. The hypothesis that higher photosynthetic nitrogen use efficiency (PNUE) in C(4) than in C(3) species allows greater flexibility in the partitioning of growth, especially under nutrient-deficient conditions, is tested here. Our experiment applied three levels of N supply to the subtropical grass Alloteropsis semialata, a unique model system with C(3) and C(4) subspecies. Photosynthesis was significantly higher for the same investment of leaf N in the C(4) than C(3) subspecies, and was unaffected by N treatments. The C(4) plants produced more biomass than the C(3) plants at high N levels, diverting a greater fraction of growth into inflorescences and corms, but less into roots and leaves. However, N-limitation of biomass production caused size-dependent shifts in the partitioning of growth. Root production was higher in small than large plants, and associated with decreasing leaf biomass in the C(3), and inflorescence production in the C(4) plants. Higher PNUE in the C(4) than C(3) subspecies was therefore linked with greater investment in sexual reproduction and storage, and the avoidance of N-limitations on leaf growth, suggesting advantages of the C(4) pathway in disturbed and infertile ecosystems.     

Six new recombinant inbred populations for the study of quantitative traits in Arabidopsis thaliana

Quantitative approaches are now widely used to study the genetic architecture of complex traits. However, most studies have been conducted in single mapping populations, which sample only a fraction of the natural allelic variation available within a gene pool and can identify only a subset of the loci controlling the traits. To enable the progress towards an understanding of the global genetic architecture of a broad range of complex traits, we have developed and characterised six new Arabidopsis thaliana recombinant inbred populations. To evaluate the utility of these populations for integrating analyses from multiple populations, we identified quantitative trait loci (QTL) controlling flowering time in vernalized plants growing in 16 h days. We used the physical positions of markers to align the linkage maps of our populations with those of six existing populations. We identified seven QTL in genomic locations coinciding with those identified in previous studies and in addition a further eight QTL were identified. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. An erratum to this article can be found at