Elixirs of death

Substandard and fake drugs are increasingly threatening lives in both the developed and developing world, but governments and industry are struggling to improve the situation.When people take medicine, they assume that it will make them better. However many patients cannot trust their drugs to be effective or even safe. Fake or substandard medicine is a major public health problem and it seems to be growing. More than 200 heart patients died in Pakistan in 2012 after taking a contaminated drug against hypertension [1]. In 2006, cough syrup that contained diethylene glycol as a cheap substitute for pharmaceutical-grade glycerin was distributed in Panama, causing the death of at least 219 people [2,3]. However, the problem is not restricted to developing countries. In 2012, more than 500 patients came down with fungal meningitis and several dozens died after receiving contaminated steroid injections from a compounding pharmacy in Massachusetts [4]. The same year, a fake version of the anti-cancer drug Avastin, which contained no active ingredient, was sold in the USA. The drug seemed to have entered the country through Turkey, Switzerland, Denmark and the UK [5].…many patients cannot trust their drugs to be effective or even safeThe extent of the problem is not really known, as companies and governments do not always report incidents [6]. However, the information that is available is alarming enough, especially in developing countries. One study found that 20% of antihypertensive drugs collected from pharmacies in Rwanda were substandard [7]. Similarly, in a survey of anti-malaria drugs in Southeast Asia and sub-Saharan Africa, 20–42% were found to be either of poor quality or outright fake [8], whilst 56% of amoxicillin capsules sampled in different Arab countries did not meet the US Pharmacopeia requirements [9].Developing countries are particularly susceptible to substandard and fake medicine. Regulatory authorities do not have the means or human resources to oversee drug manufacturing and distribution. A country plagued by civil war or famine might have more pressing problems—including shortages of medicine in the first place. The drug supply chain is confusingly complex with medicines passing through many different hands before they reach the patient, which creates many possible entry points for illegitimate products. Many people in developing countries live in rural areas with no local pharmacy, and anyway have little money and no health insurance. Instead, they buy cheap medicine from street vendors at the market or on the bus (Fig 1; [2,10,11]). “People do not have the money to buy medicine at a reasonable price. But quality comes at a price. A reasonable margin is required to pay for a quality control system,” explained Hans Hogerzeil, Professor of Global Health at Groningen University in the Netherlands. In some countries, falsifying medicine has developed into a major business. The low risk of being detected combined with relatively low penalties has turned falsifying medicine into the “perfect crime” [2].Open in a separate windowFigure 1Women sell smuggled, counterfeit medicine on the Adjame market in Abidjan, Ivory Coast, in 2007. Fraudulent street medecine sales rose by 15–25% in the past two years in Ivory Coast.Issouf Sanogo/AFP Photo/Getty Images.There are two main categories of illegitimate drugs. ‘Substandard'' medicines might result from poor-quality ingredients, production errors and incorrect storage. ‘Falsified'' medicine is made with clear criminal intent. It might be manufactured outside the regulatory system, perhaps in an illegitimate production shack that blends chalk with other ingredients and presses it into pills [10]. Whilst falsified medicines do not typically contain any active ingredients, substandard medicine might contain subtherapeutic amounts. This is particularly problematic when it comes to anti-infectious drugs, as it facilitates the emergence and spread of drug resistance [12]. A sad example is the emergence of artemisinin-resistant Plasmodium strains at the Thai–Cambodia border [8] and the Thai–Myanmar border [13], and increasing multidrug-resistant tuberculosis might also be attributed to substandard medication [11].Many people in developing countries live in rural areas with no local pharmacy, and anyway have little money and no health insuranceEven if a country effectively prosecutes falsified and substandard medicine within its borders, it is still vulnerable to fakes and low-quality drugs produced elsewhere where regulations are more lax. To address this problem, international initiatives are urgently required [10,14,15], but there is no internationally binding law to combat counterfeit and substandard medicine. Although drug companies, governments and NGOs are interested in good-quality medicines, the different parties seem to have difficulties coming to terms with how to proceed. What has held up progress is a conflation of health issues and economic interests: innovator companies and high-income countries have been accused of pushing for the enforcement of intellectual property regulations under the guise of protecting quality of medicine [14,16].The concern that intellectual property (IP) interests threaten public health dates back to the ‘Trade-Related Aspects of Intellectual Property Rights (TRIPS) Agreement'' of the World Trade Organization (WTO), adopted in 1994, to establish global protection of intellectual property rights, including patents for pharmaceuticals. The TRIPS Agreement had devastating consequences during the acquired immunodeficiency syndrome epidemic, as it blocked patients in developing countries from access to affordable medicine. Although it includes flexibility, such as the possibility for governments to grant compulsory licenses to manufacture or import a generic version of a patented drug, it has not always been clear how these can be used by countries [14,16,17].In response to public concerns over the public health consequences of TRIPS, the Doha Declaration on the TRIPS Agreement and Public Health was adopted at the WTO''s Ministerial Conference in 2001. It reaffirmed the right of countries to use TRIPS flexibilities and confirmed the primacy of public health over the enforcement of IP rights. Although things have changed for the better, the Doha Declaration did not solve all the problems associated with IP protection and public health. For example, anti-counterfeit legislation, encouraged by multi-national pharmaceutical industries and the EU, threatened to impede the availability of generic medicines in East Africa [14,16,18]. In 2008–2009, European customs authorities seized shipments of legitimate generic medicines in transit from India to other developing countries because they infringed European IP laws [14,16,17]. “We''re left with decisions being taken based on patents and trademarks that should be taken based on health,” commented Roger Bate, a global health expert and resident scholar at the American Enterprise Institute in Washington, USA. “The health community is shooting themselves in the foot.”Conflating health care and IP issues are reflected in the unclear use of the term ‘counterfeit'' [2,14]. “Since the 1990s the World Health Organization (WHO) has used the term ‘counterfeit'' in the sense we now use ‘falsified'',” explained Hogerzeil. “The confusion started in 1995 with the TRIPS agreement, through which the term ‘counterfeit'' got the very narrow meaning of trademark infringement.” As a consequence, an Indian generic, for example, which is legal in some countries but not in others, could be labelled as ‘counterfeit''—and thus acquire the negative connotation of bad quality. “The counterfeit discussion was very much used as a way to block the market of generics and to put them in a bad light,” Hogerzeil concluded.The rifts between the stakeholders have become so deep during the course of these discussions that progress is difficult to achieve. “India is not at all interested in any international regulation. And, unfortunately, it wouldn''t make much sense to do anything without them,” Hogerzeil explained. Indeed, India is a core player: not only does it have a large generics industry, but also the country seems to be, together with China, the biggest source of fake medical products [19,20]. The fact that India is so reluctant to react is tragically ironic, as this stance hampers the growth of its own generic companies like Ranbaxy, Cipla or Piramal. “I certainly don''t believe that Indian generics would lose market share if there was stronger action on public health,” Bate said. Indeed, stricter regulations and control systems would be advantageous, because they would keep fakers at bay. The Indian generic industry is a common target for fakers, because their products are broadly distributed. “The most likely example of a counterfeit product I have come across in emerging markets is a counterfeit Indian generic,” Bate said. Such fakes can damage a company''s reputation and have a negative impact on its revenues when customers stop buying the product.The WHO has had a key role in attempting to draft international regulations that would contain the spread of falsified and substandard medicine. It took a lead in 2006 with the launch of the International Medical Products Anti-Counterfeiting Taskforce (IMPACT). But IMPACT was not a success. Concerns were raised over the influence of multi-national drug companies and the possibility that issues on quality of medicines were conflated with the attempts to enforce stronger IP measures [17]. The WHO distanced itself from IMPACT after 2010. For example, it no longer hosts IMPACT''s secretariat at its headquarters in Geneva [2].‘Substandard'' medicines might result from poor quality ingredients, production errors and incorrect storage. ‘Falsified'' medicine is made with clear criminal intentIn 2010, the WHO''s member states established a working group to further investigate how to proceed, which led to the establishment of a new “Member State mechanism on substandard/spurious/falsely labelled/falsified/counterfeit medical products” (http://www.who.int/medicines/services/counterfeit/en/index.html). However, according to a publication by Amir Attaran from the University of Ottawa, Canada, and international colleagues, the working group “still cannot agree how to define the various poor-quality medicines, much less settle on any concrete actions” [14]. The paper''s authors demand more action and propose a binding legal framework: a treaty. “Until we have stronger public health law, I don''t think that we are going to resolve this problem,” Bate, who is one of the authors of the paper, said.Similarly, the US Food and Drug Administration (FDA) commissioned the Institute of Medicine (IOM) to convene a consensus committee on understanding the global public health implications of falsified and substandard pharmaceuticals [2]. Whilst others have called for a treaty, the IOM report calls on the World Health Assembly—the governing body of the WHO—to develop a code of practice such as a “voluntary soft law” that countries can sign to express their will to do better. “At the moment, there is not yet enough political interest in a treaty. A code of conduct may be more realistic,” Hogerzeil, who is also on the IOM committee, commented. Efforts to work towards a treaty should nonetheless be pursued, Bate insisted: “The IOM is right in that we are not ready to sign a treaty yet, but that does not mean you don''t start negotiating one.”Whilst a treaty might take some time, there are several ideas from the IOM report and elsewhere that could already be put into action to deal with this global health threat [10,12,14,15,19]. Any attempts to safeguard medicines need to address both falsified and substandard medicines, but the counter-measures are different [14]. Falsifying medicine is, by definition, a criminal act. To counteract fakers, action needs to be taken to ensure that the appropriate legal authorities deal with criminals. Substandard medicine, on the other hand, arises when mistakes are made in genuine manufacturing companies. Such mistakes can be reduced by helping companies do better and by improving quality control of drug regulatory authorities.Manufacturing pharmaceuticals is a difficult and costly business that requires clean water, high-quality chemicals, expensive equipment, technical expertise and distribution networks. Large and multi-national companies benefit from economies of scale to cope with these problems. But smaller companies often struggle and compromise in quality [2,21]. “India has 20–40 big companies and perhaps nearly 20,000 small ones. To me, it seems impossible for them to produce at good quality, if they remain so small,” Hogerzeil explained. “And only by being strict, can you force them to combine and to become bigger industries that can afford good-quality assurance systems.” Clamping down on drug quality will therefore lead to a consolidation of the industry, which is an essential step. “If you look at Europe and the US, there were hundreds of drug companies—now there are dozens. And if you look at the situation in India and China today, there are thousands and that will have to come down to dozens as well,” Bate explained.…innovator companies and high-income countries have been accused of pushing for the enforcement of intellectual property regulations under the guise of protecting […] medicineIn addition to consolidating the market by applying stricter rules, the IOM has also suggested measures for supporting companies that observe best practices [2]. For example, the IOM proposes that the International Finance Corporation and the Overseas Private Investment Corporation, which promote private-sector development to reduce poverty, should create separate investment vehicles for pharmaceutical manufacturers who want to upgrade to international standards. Another suggestion is to harmonize market registration of pharmaceutical products, which would ease the regulatory burden for generic producers in developing countries and improve the efficiency of regulatory agencies.Once the medicine leaves the manufacturer, controlling distribution systems becomes another major challenge in combatting falsified and substandard medicine. Global drug supply chains have grown increasingly complicated; drugs cross borders, are sold back and forth between wholesalers and distributers, and are often repackaged. Still, there is a main difference between developing and developed countries. In the latter case, relatively few companies dominate the market, whereas in poorer nations, the distribution system is often fragmented and uncontrolled with parallel schemes, too few pharmacies, even fewer pharmacists and many unlicensed medical vendors. Every transaction creates an opportunity for falsified or substandard medicine to enter the market [2,10,19]. More streamlined and transparent supply chains and stricter licensing requirements would be crucial to improve drug quality. “And we can start in the US,” Hogerzeil commented.…India is a core player: not only does it have a large generics industry, but the country also seems to be, together with China, the biggest source of fake medical productsDistribution could be improved at different levels, starting with the import of medicine. “There are states in the USA where the regulation for medicine importation is very lax. Anyone can import; private clinics can buy medicine from Lebanon or elsewhere and fly them in,” Hogerzeil explained. The next level would be better control over the distribution system within the country. The IOM suggests that state boards should license wholesalers and distributors that meet the National Association of Boards of Pharmacy accreditation standards. “Everybody dealing with medicine has to be licensed,” Hogerzeil said. “And there should be a paper trail of who buys what from whom. That way you close the entry points for illegal drugs and prevent that falsified medicines enter the legal supply chain.” The last level would be a track-and-trace system to identify authentic drugs [2]. Every single package of medicine should be identifiable through an individual marker, such as a 3D bar code. Once it is sold, it is ticked off in a central database, so the marker cannot be reused.According to Hogerzeil, equivalent measures at these different levels should be established in every country. “I don''t believe in double standards”, he said. “Don''t say to Uganda: ‘you can''t do that''. Rather, indicate to them what a cost-effective system in the West looks like and help them, and give them the time, to create something in that direction that is feasible in their situation.”Nigeria, for instance, has demonstrated that with enough political will, it is possible to reduce the proliferation of falsified and substandard medicine. Nigeria had been a major source for falsified products, but things changed in 2001, when Dora Akunyili was appointed Director General of the National Agency for Food and Drug Administration and Control. Akunyili has a personal motivation for fighting falsified drugs: her sister Vivian, a diabetic patient, lost her life to fake insulin in 1988. Akunyili strengthened import controls, campaigned for public awareness, clamped down on counterfeit operations and pushed for harsher punishments [10,19]. Paul Orhii, Akunyili''s successor, is committed to continuing her work [10]. Although there are no exact figures, various surveys indicate that the rate of bad-quality medicine has dropped considerably in Nigeria [10].China is also addressing its drug-quality problems. In a highly publicized event, the former head of China''s State Food and Drug Administration, Zheng Xiaoyu, was executed in 2007 after he was found guilty of accepting bribes to approve untested medicine. Since then, China''s fight against falsified medicine has continued. As a result of heightened enforcement, the number of drug companies in China dwindled from 5,000 in 2004 to about 3,500 this year [2]. Moreover, in July 2012, more than 1,900 suspects were arrested for the sale of fake or counterfeit drugs.Quality comes at a price, however. It is expensive to produce high-quality medicine, and it is expensive to control the production and distribution of drugs. Many low- and middle-income countries might not have the resources to tackle the problem and might not see quality of medicine as a priority. But they should, and affluent countries should help. Not only because health is a human right, but also for economic reasons. A great deal of time and money is invested into testing the safety and efficacy of medicine during drug development, and these resources are wasted when drugs do not reach patients. Falsified and substandard medicines are a financial burden to health systems and the emergence of drug-resistant pathogens might make invaluable medications useless. Investing in the safety of medicine is therefore a humane and an economic imperative.     

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     

Scientific dissent and public policy

The temptation to silence dissenters whose non-mainstream views negatively affect public policies is powerful. However, silencing dissent, no matter how scientifically unsound it might be, can cause the public to mistrust science in general.Dissent is crucial for the advancement of science. Disagreement is at the heart of peer review and is important for uncovering unjustified assumptions, flawed methodologies and problematic reasoning. Enabling and encouraging dissent also helps to generate alternative hypotheses, models and explanations. Yet, despite the importance of dissent in science, there is growing concern that dissenting voices have a negative effect on the public perception of science, on policy-making and public health. In some cases, dissenting views are deliberately used to derail certain policies. For example, dissenting positions on climate change, environmental toxins or the hazards of tobacco smoke [1,2] seem to laypeople as equally valid conflicting opinions and thereby create or increase uncertainty. Critics often use legitimate scientific disagreements about narrow claims to reinforce the impression of uncertainty about general and widely accepted truths; for instance, that a given substance is harmful [3,4]. This impression of uncertainty about the evidence is then used to question particular policies [1,2,5,6].The negative effects of dissent on establishing public polices are present in cases in which the disagreements are scientifically well-grounded, but the significance of the dissent is misunderstood or blown out of proportion. A study showing that many factors affect the size of reef islands, to the effect that they will not necessarily be reduced in size as sea levels rise [7], was simplistically interpreted by the media as evidence that climate change will not have a negative impact on reef islands [8].In other instances, dissenting voices affect the public perception of and motivation to follow public-health policies or recommendations. For example, the publication of a now debunked link between the measles, mumps and rubella vaccine and autism [9], as well as the claim that the mercury preservative thimerosal, which was used in childhood vaccines, was a possible risk factor for autism [10,11], created public doubts about the safety of vaccinating children. Although later studies showed no evidence for these claims, doubts led many parents to reject vaccinations for their children, risking the herd immunity for diseases that had been largely eradicated from the industrialized world [12,13,14,15]. Many scientists have therefore come to regard dissent as problematic if it has the potential to affect public behaviour and policy-making. However, we argue that such concerns about dissent as an obstacle to public policy are both dangerous and misguided.Whether dissent is based on genuine scientific evidence or is unfounded, interested parties can use it to sow doubt, thwart public policies, promote problematic alternatives and lead the public to ignore sound advice. In response, scientists have adopted several strategies to limit these negative effects of dissent—masking dissent, silencing dissent and discrediting dissenters. The first strategy aims to present a united front to the public. Scientists mask existing disagreements among themselves by presenting only those claims or pieces of evidence about which they agree [16]. Although there is nearly universal agreement among scientists that average global temperatures are increasing, there are also legitimate disagreements about how much warming will occur, how quickly it will occur and the impact it might have [7,17,18,19]. As presenting these disagreements to the public probably creates more doubt and uncertainty than is warranted, scientists react by presenting only general claims [20].A second strategy is to silence dissenting views that might have negative consequences. This can take the form of self-censorship when scientists are reluctant to publish or publicly discuss research that might—incorrectly—be used to question existing scientific knowledge. For example, there are genuine disagreements about how best to model cloud formation, water vapour feedback and aerosols in general circulation paradigms, all of which have significant effects on the magnitude of global climate change predictions [17,19]. Yet, some scientists are hesitant to make these disagreements public, for fear that they will be accused of being denialists, faulted for confusing the public and policy-makers, censured for abating climate-change deniers, or criticized for undermining public policy [21,22,23,24].…there is growing concern that dissenting voices can have a negative effect on the public perception of science, on policy-making and public healthAnother strategy is to discredit dissenters, especially in cases in which the dissent seems to be ideologically motivated. This could involve publicizing the financial or political ties of the dissenters [2,6,25], which would call attention to their probable bias. In other cases, scientists might discredit the expertise of the dissenter. One such example concerns a 2007 study published in the Proceedings of the National Academy of Sciences USA, which claimed that cadis fly larvae consuming Bt maize pollen die at twice the rate of flies feeding on non-Bt maize pollen [26]. Immediately after publication, both the authors and the study itself became the target of relentless and sometimes scathing attacks from a group of scientists who were concerned that anti-GMO (genetically modified organism) interest groups would seize on the study to advance their agenda [27]. The article was criticized for its methodology and its conclusions, the Proceedings of the National Academy of Sciences USA was criticized for publishing the article and the US National Science Foundation was criticized for funding the study in the first place.Public policies, health advice and regulatory decisions should be based on the best available evidence and knowledge. As the public often lack the expertise to assess the quality of dissenting views, disagreements have the potential to cast doubt over the reliability of scientific knowledge and lead the public to question relevant policies. Strategies to block dissent therefore seem reasonable as a means to protect much needed or effective health policies, advice and regulations. However, even if the public were unable to evaluate the science appropriately, targeting dissent is not the most appropriate strategy to prevent negative side effects for several reasons. Chiefly, it contributes to the problems that the critics of dissent seek to address, namely increasing the cacophony of dissenting voices that only aim to create doubt. Focusing on dissent as a problematic activity sends the message to policy-makers and the public that any dissent undermines scientific knowledge. Reinforcing this false assumption further incentivizes those who seek merely to create doubt to thwart particular policies. Not surprisingly, think-tanks, industry and other organizations are willing to manufacture dissent simply to derail policies that they find economically or ideologically undesirable.Another danger of targeting dissent is that it probably stifles legitimate crucial voices that are needed for both advancing science and informing sound policy decisions. Attacking dissent makes scientists reluctant to voice genuine doubts, especially if they believe that doing so might harm their reputations, damage their careers and undermine prevailing theories or policies needed. For instance, a panel of scientists for the US National Academy of Sciences, when presenting a risk assessment of radiation in 1956, omitted wildly different predictions about the potential genetic harm of radiation [16]. They did not include this wide range of predictions in their final report precisely because they thought the differences would undermine confidence in their recommendations. Yet, this information could have been relevant to policy-makers. As such, targeting dissent as an obstacle to public policy might simply reinforce self-censorship and stifle legitimate and scientifically informed debate. If this happens, scientific progress is hindered.Second, even if the public has mistaken beliefs about science or the state of the knowledge of the science in question, focusing on dissent is not an effective way to protect public policy from false claims. It fails to address the presumed cause of the problem—the apparent lack of understanding of the science by the public. A better alternative would be to promote the public''s scientific literacy. If the public were educated to better assess the quality of the dissent and thus disregard instances of ideological, unsupported or unsound dissent, dissenting voices would not have such a negative effect. Of course, one might argue that educating the public would be costly and difficult, and that therefore, the public should simply listen to scientists about which dissent to ignore and which to consider. This is, however, a paternalistic attitude that requires the public to remain ignorant ‘for their own good''; a position that seems unjustified on many levels as there are better alternatives for addressing the problem.Moreover, silencing dissent, rather than promoting scientific literacy, risks undermining public trust in science even if the dissent is invalid. This was exemplified by the 2009 case of hacked e-mails from a computer server at the University of East Anglia''s Climate Research Unit (CRU). After the selective leaking of the e-mails, climate scientists at the CRU came under fire because some of the quotes, which were taken out of context, seemed to suggest that they were fudging data or suppressing dissenting views [28,29,30,31]. The stolen e-mails gave further ammunition to those opposing policies to reduce greenhouse emissions as they could use accusations of data ‘cover up'' as proof that climate scientists were not being honest with the public [29,30,31]. It also allowed critics to present climate scientists as conspirators who were trying to push a political agenda [32]. As a result, although there was nothing scientifically inappropriate revealed in the ‘climategate'' e-mails, it had the consequence of undermining the public''s trust in climate science [33,34,35,36].A significant amount of evidence shows that the ‘deficit model'' of public understanding of science, as described above, is too simplistic to account correctly for the public''s reluctance to accept particular policy decisions [37,38,39,40]. It ignores other important factors such as people''s attitudes towards science and technology, their social, political and ethical values, their past experiences and the public''s trust in governmental institutions [41,42,43,44]. The development of sound public policy depends not only on good science, but also on value judgements. One can agree with the scientific evidence for the safety of GMOs, for instance, but still disagree with the widespread use of GMOs because of social justice concerns about the developing world''s dependence on the interests of the global market. Similarly, one need not reject the scientific evidence about the harmful health effects of sugar to reject regulations on sugary drinks. One could rationally challenge such regulations on the grounds that informed citizens ought to be able to make free decisions about what they consume. Whether or not these value judgements are justified is an open question, but the focus on dissent hinders our ability to have that debate.Focusing on dissent as a problematic activity sends the message to policy-makers and the public that any dissent undermines scientific knowledgeAs such, targeting dissent completely fails to address the real issues. The focus on dissent, and the threat that it seems to pose to public policy, misdiagnoses the problem as one of the public misunderstanding science, its quality and its authority. It assumes that scientific or technological knowledge is the only relevant factor in the development of policy and it ignores the role of other factors, such as value judgements about social benefits and harms, and institutional trust and reliability [45,46]. The emphasis on dissent, and thus on scientific knowledge, as the only or main factor in public policy decisions does not give due attention to these legitimate considerations.Furthermore, by misdiagnosing the problem, targeting dissent also impedes more effective solutions and prevents an informed debate about the values that should guide public policy. By framing policy debates solely as debates over scientific facts, the normative aspects of public policy are hidden and neglected. Relevant ethical, social and political values fail to be publicly acknowledged and openly discussed.Controversies over GMOs and climate policies have called attention to the negative effects of dissent in the scientific community. Based on the assumption that the public''s reluctance to support particular policies is the result of their inability to properly understand scientific evidence, scientists have tried to limit dissenting views that create doubt. However, as outlined above, targeting dissent as an obstacle to public policy probably does more harm than good. It fails to focus on the real problem at stake—that science is not the only relevant factor in sound policy-making. Of course, we do not deny that scientific evidence is important to the develop.ment of public policy and behavioural decisions. Rather, our claim is that this role is misunderstood and often oversimplified in ways that actually contribute to problems in developing sound science-based policies.? Open in a separate windowInmaculada de Melo-MartínOpen in a separate windowKristen Intemann     

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.     

The academic birth rate. Production and reproduction of the research work force, and its effect on innovation and research misconduct

Universities have been churning out PhD students to reap financial and other rewards for training biomedical scientists. This deluge of cheap labour has created unhealthy competition, which encourages scientific misconduct.Most developed nations invest a considerable amount of public money in scientific research for a variety of reasons: most importantly because research is regarded as a motor for economic progress and development, and to train a research workforce for both academia and industry. Not surprisingly, governments are occasionally confronted with questions about whether the money invested in research is appropriate and whether taxpayers are getting the maximum value for their investments.…questions about the size and composition of the research workforce have historically been driven by concerns that the system produces an insufficient number of scientistsThe training and maintenance of the research workforce is a large component of these investments. Yet discussions in the USA about the appropriate size of this workforce have typically been contentious, owing to an apparent lack of reliable data to tell us whether the system yields academic ‘reproduction rates'' that are above, below or at replacement levels. In the USA, questions about the size and composition of the research workforce have historically been driven by concerns that the system produces an insufficient number of scientists. As Donald Kennedy, then Editor-in-Chief of Science, noted several years ago, leaders in prestigious academic institutions have repeatedly rung alarm bells about shortages in the science workforce. Less often does one see questions raised about whether too many scientists are being produced or concerns about unintended consequences that may result from such overproduction. Yet recognizing that resources are finite, it seems reasonable to ask what level of competition for resources is productive, and at what level does competition become counter-productive.Finding a proper balance between the size of the research workforce and the resources available to sustain it has other important implications. Unhealthy competition—too many people clamouring for too little money and too few desirable positions—creates its own problems, most notably research misconduct and lower-quality, less innovative research. If an increasing number of scientists are scrambling for jobs and resources, some might begin to cut corners in order to gain a competitive edge. Moreover, many in the science community worry that every publicized case of research misconduct could jeopardize those resources, if politicians and taxpayers become unwilling to invest in a research system that seems to be riddled with fraud and misconduct.The biomedical research enterprise in the USA provides a useful context in which to examine the level of competition for resources among academic scientists. My thesis is that the system of publicly funded research in the USA as it is currently configured supports a feedback system of institutional incentives that generate excessive competition for resources in biomedical research. These institutional incentives encourage universities to overproduce graduate students and postdoctoral scientists, who are both trainees and a cheap source of skilled labour for research while in training. However, once they have completed their training, they become competitors for money and positions, thereby exacerbating competitive pressures.Questions raised about whether too many scientists are being produced or concerns about the unintended consequences of such overproduction are less commonThe resulting scarcity of resources, partly through its effect on peer review, leads to a shunting of resources away from both younger researchers and the most innovative ideas, which undermines the effectiveness of the research enterprise as a whole. Faced with an increasing number of grant applications and the consequent decrease in the percentage of projects that can be funded, reviewers tend to ‘play it safe'' and favour projects that have a higher likelihood of yielding results, even if the research is conservative in the sense that it does not explore new questions. Resource scarcity can also introduce unwanted randomness to the process of determining which research gets funded. A large group of scientists, led by a cancer biologist, has recently mounted a campaign against a change in a policy of the National Institutes of Health (NIH) to allow only one resubmission of an unfunded grant proposal (Wadman, 2011). The core of their argument is that peer reviewers are likely able to distinguish the top 20% of research applications from the rest, but that within that top 20%, distinguishing the top 5% or 10% means asking peer reviewers for a level of precision that is simply not possible. With funding levels in many NIH institutes now within that 5–10% range, the argument is that reviewers are being forced to choose at random which excellent applications do and do not get funding. In addition to the inefficiency of overproduction and excessive competition in terms of their costs to society and opportunity costs to individuals, these institutional incentives might undermine the integrity and quality of science, and reduce the likelihood of breakthroughs.My colleagues and I have expressed such concerns about workforce dynamics and related issues in several publications (Martinson, 2007; Martinson et al, 2005, 2006, 2009, 2010). Early on, we observed that, “missing from current analyses of scientific integrity is a consideration of the wider research environment, including institutional and systemic structures” (Martinson et al, 2005). Our more recent publications have been more specific about the institutional and systemic structures concerned. It seems that at least a few important leaders in science share these concerns.In April 2009, the NIH, through the National Institute of General Medical Sciences (NIGMS), issued a request for applications (RFA) calling for proposals to develop computational models of the research workforce (http://grants.nih.gov/grants/guide/rfa-files/RFA-GM-10-003.html). Although such an initiative might be premature given the current level of knowledge, the rationale behind the RFA seems irrefutable: “there is a need to […] pursue a systems-based approach to the study of scientific workforce dynamics.” Roughly four decades after the NIH appeared on the scene, this is, to my knowledge, the first official, public recognition that the biomedical workforce tends not to conform nicely to market forces of supply and demand, despite the fact that others have previously made such arguments.Early last year, Francis Collins, Director of the NIH, published a PolicyForum article in Science, voicing many of the concerns I have expressed about specific influences that have led to growth rates in the science workforce that are undermining the effectiveness of research in general, and biomedical research in particular. He notes the increasing stress in the biomedical research community after the end of the NIH “budget doubling” between 1998 and 2003, and the likelihood of further disruptions when the American Recovery and Reinvestment Act of 2009 (ARRA) funding ends in 2011. Arguing that innovation is crucial to the future success of biomedical research, he notes the tendency towards conservatism of the NIH peer-review process, and how this worsens in fiscally tight times. Collins further highlights the ageing of the NIH workforce—as grants increasingly go to older scientists—and the increasing time that researchers are spending in itinerant and low-paid postdoctoral positions as they stack up in a holding pattern, waiting for faculty positions that may or may not materialize. Having noted these challenging trends, and echoing the central concerns of a 2007 Nature commentary (Martinson, 2007), he concludes that “…it is time for NIH to develop better models to guide decisions about the optimum size and nature of the US workforce for biomedical research. A related issue that needs attention, though it will be controversial, is whether institutional incentives in the current system that encourage faculty to obtain up to 100% of their salary from grants are the best way to encourage productivity.”Similarly, Bruce Alberts, Editor-in-Chief of Science, writing about incentives for innovation, notes that the US biomedical research enterprise includes more than 100,000 graduate students and postdoctoral fellows. He observes that “only a select few will go on to become independent research scientists in academia”, and argues that “assuming that the system supporting this career path works well, these will be the individuals with the most talent and interest in such an endeavor” (Alberts, 2009).His editorial is not concerned with what happens to the remaining majority, but argues that even among the select few who manage to succeed, the funding process for biomedical research “forces them to avoid risk-taking and innovation”. The primary culprit, in his estimation, is the conservatism of the traditional peer-review system for federal grants, which values “research projects that are almost certain to ‘work''”. He continues, “the innovation that is essential for keeping science exciting and productive is replaced by […] research that has little chance of producing the breakthroughs needed to improve human health.”If an increasing number of scientists are scrambling for jobs and resources, some might begin to cut corners in order to gain a competitive edgeAlthough I believe his assessment of the symptoms is correct, I think he has misdiagnosed the cause, in part because he has failed to identify which influence he is concerned with from the network of influences in biomedical research. To contextualize the influences of concern to Alberts, we must consider the remaining majority of doctorally trained individuals so easily dismissed in his editorial, and further examine what drives the dynamics of the biomedical research workforce.Labour economists might argue that market forces will always balance the number of individuals with doctorates with the number of appropriate jobs for them in the long term. Such arguments would ignore, however, the typical information asymmetry between incoming graduate students, whose knowledge about their eventual job opportunities and career options is by definition far more limited than that of those who run the training programmes. They would also ignore the fact that universities are generally not confronted with the externalities resulting from overproduction of PhDs, and have positive financial incentives that encourage overproduction. During the past 40 years, NIH ‘extramural'' funding has become crucial for graduate student training, faculty salaries and university overheads. For their part, universities have embraced NIH extramural funding as a primary revenue source that, for a time, allowed them to implement a business model based on the interconnected assumptions that, as one of the primary ‘outputs'' or ‘products'' of the university, more doctorally trained individuals are always better than fewer, and because these individuals are an excellent source of cheap, skilled labour during their training, they help to contain the real costs of faculty research.“…the current system has succeeded in maximizing the amount of research […] it has also degraded the quality of graduate training and led to an overproduction of PhDs…”However, it has also made universities increasingly dependent on NIH funding. As recently documented by the economist Paula Stephan, most faculty growth in graduate school programmes during the past decade has occurred in medical colleges, with the majority—more than 70%—in non-tenure-track positions. Arguably, this represents a shift of risk away from universities and onto their faculty. Despite perennial cries of concern about shortages in the research workforce (Butz et al, 2003; Kennedy et al, 2004; National Academy of Sciences et al, 2005) a number of commentators have recently expressed concerns that the current system of academic research might be overbuilt (Cech, 2005; Heinig et al, 2007; Martinson, 2007; Stephan, 2007). Some explicitly connect this to structural arrangements between the universities and NIH funding (Cech, 2005; Collins, 2007; Martinson, 2007; Stephan, 2007).In 1995, David Korn pointed out what he saw as some problematic aspects of the business model employed by Academic Medical Centers (AMCs) in the USA during the past few decades (Korn, 1995). He noted the reliance of AMCs on the relatively low-cost, but highly skilled labour represented by postdoctoral fellows, graduate students and others—who quickly start to compete with their own professors and mentors for resources. Having identified the economic dependence of the AMCs on these inexpensive labour pools, he noted additional problems with the graduate training programmes themselves. “These programs are […] imbued with a value system that clearly indicates to all participants that true success is only marked by the attainment of a faculty position in a high-profile research institution and the coveted status of principal investigator on NIH grants.” Pointing to “more than 10 years of severe supply/demand imbalance in NIH funds”, Korn concluded that, “considering the generative nature of each faculty mentor, this enterprise could only sustain itself in an inflationary environment, in which the society''s investment in biomedical research and clinical care was continuously and sharply expanding.” From 1994 to 2003, total funding for biomedical research in the USA increased at an annual rate of 7.8%, after adjustment for inflation. The comparable rate of growth between 2003 and 2007 was 3.4% (Dorsey et al, 2010). These observations resonate with the now classic observation by Derek J. de Solla Price, from more than 30 years before, that growth in science frequently follows an exponential pattern that cannot continue indefinitely; the enterprise must eventually come to a plateau (de Solla Price, 1963).In May 2009, echoing some of Korn''s observations, Nobel laureate Roald Hoffmann caused a stir in the US science community when he argued for a “de-coupling” of the dual roles of graduate students as trainees and cheap labour (Hoffmann, 2009). His suggestion was to cease supporting graduate students with faculty research grants, and to use the money instead to create competitive awards for which graduate students could apply, making them more similar to free agents. During the ensuing discussion, Shirley Tilghman, president of Princeton University, argued that “although the current system has succeeded in maximizing the amount of research performed […] it has also degraded the quality of graduate training and led to an overproduction of PhDs in some areas. Unhitching training from research grants would be a much-needed form of professional ‘birth control''” (Mervis, 2009).The greying of the NIH research workforce is another important driver of workforce dynamics, and it is integrally linked to the fate of young scientistsAlthough the issue of what I will call the ‘academic birth rate'' is the central concern of this analysis, the ‘academic end-of-life'' also warrants some attention. The greying of the NIH research workforce is another important driver of workforce dynamics, and it is integrally linked to the fate of young scientists. A 2008 news item in Science quoted then 70-year-old Robert Wells, a molecular geneticist at Texas A&M University, “‘if I and other old birds continue to land the grants, the [young scientists] are not going to get them.” He worries that the budget will not be able to support “the 100 people ‘I''ve trained […] to replace me''” (Kaiser, 2008). While his claim of 100 trainees might be astonishing, it might be more astonishing that his was the outlying perspective. The majority of senior scientists interviewed for that article voiced intentions to keep doing science—and going after NIH grants—until someone forced them to stop or they died.Some have looked at the current situation with concern, primarily because of the threats it poses to the financial and academic viability of universities (Korn, 1995; Heinig et al, 2007; Korn & Heinig, 2007), although most of those who express such concerns have been distinctly reticent to acknowledge the role of universities in creating and maintaining the situation. Others have expressed concerns about the differential impact of extreme competition and meagre job prospects on the recruitment, development and career survival of young and aspiring scientists (Freeman et al, 2001; Kennedy et al, 2004; Martinson et al, 2006; Anderson et al, 2007a; Martinson, 2007; Stephan, 2007). There seems to be little disagreement, however, that the system has generated excessively high competition for federal research funding, and that this threatens to undermine the very innovation and production of knowledge that is its raison d''etre.The production of knowledge in science, particularly of the ‘revolutionary'' variety, is generally not a linear input–output process with predictable returns on investment, clear timelines and high levels of certainty (Lane, 2009). On the contrary, it is arguable that “revolutionary science is a high risk and long-term endeavour which usually fails” (Charlton & Andras, 2008). Predicting where, when and by whom breakthroughs in understanding will be produced has proven to be an extremely difficult task. In the face of such uncertainty, and denying the realities of finite resources, some have argued that the best bet is to maximize the number of scientists, using that logic to justify a steady-state production of new PhDs, regardless of whether the labour market is sending signals of increasing or decreasing demand for that supply. Only recently have we begun to explore the effects of the current arrangement on the process of knowledge production, and on innovation in particular (Charlton & Andras, 2008; Kolata, 2009).…most of those who express such concerns have been reticent to acknowledge the role of universities themselves in creating and maintaining the situationBruce Alberts, in the above-mentioned editorial, points to several initiatives launched by the NIH that aim to get a larger share of NIH funding into the hands of young scientists with particularly innovative ideas. These include the “New Innovator Award,” the “Pioneer Award” and the “Transformational R01 Awards”. The proportion of NIH funding dedicated to these awards, however, amounts to “only 0.27% of the NIH budget” (Alberts, 2009). Such a small proportion of the NIH budget does not seem likely to generate a large amount of more innovative science. Moreover, to the extent that such initiatives actually succeed in enticing more young investigators to become dependent on NIH funds, any benefit these efforts have in terms of innovation may be offset by further increases in competition for resources that will come when these new ‘innovators'' reach the end of this specialty funding and add to the rank and file of those scrapping for funds through the standard mechanisms.Our studies on research integrity have been mostly oriented towards understanding how the influences within which academic scientists work might affect their behaviour, and thus the quality of the science they produce (Anderson et al, 2007a, 2007b; Martinson et al, 2009, 2010). My colleagues and I have focused on whether biomedical researchers perceive fairness in the various exchange relationships within their work systems. I am persuaded by the argument that expectations of fairness in exchange relationships have been hard-wired into us through evolution (Crockett et al, 2008; Hsu et al, 2008; Izuma et al, 2008; Pennisi, 2009), with the advent of modern markets being a primary manifestation of this. Thus, violations of these expectations strike me as potentially corrupting influences. Such violations might be prime motivators for ill will, possibly engendering bad-faith behaviour among those who perceive themselves to have been slighted, and therefore increasing the risk of research misconduct. They might also corrupt the enterprise by signalling to talented young people that biomedical research is an inhospitable environment in which to develop a career, possibly chasing away some of the most talented individuals, and encouraging a selection of characteristics that might not lead to optimal effectiveness, in terms of scientific innovation and productivity (Charlton, 2009).To the extent that we have an ecology with steep competition that is fraught with high risks of career failure for young scientists after they incur large costs of time, effort and sometimes financial resources to obtain a doctoral degree, why would we expect them to take on the additional, substantial risks involved in doing truly innovative science and asking risky research questions? And why, in such a cut-throat setting, would we not anticipate an increase in corner-cutting, and a corrosion of good scientific practice, collegiality, mentoring and sociability? Would we not also expect a reduction in high-risk, innovative science, and a reversion to a more career-safe type of ‘normal'' science? Would this not reduce the effectiveness of the institution of biomedical research? I do not claim to know the conditions needed to maximize the production of research that is novel, innovative and conducted with integrity. I am fairly certain, however, that putting scientists in tenuous positions in which their careers and livelihoods would be put at risk by pursuing truly revolutionary research is one way to insure against it.     

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.     

Risk of serious adverse cardiovascular events associated with varenicline: a systematic review and meta-analysis

Background:

There have been postmarketing reports of adverse cardiovascular events associated with the use of varenicline, a widely used smoking cessation drug. We conducted a systematic review and meta-analysis of randomized controlled trials to ascertain the serious adverse cardiovascular effects of varenicline compared with placebo among tobacco users.

Methods:

We searched MEDLINE, EMBASE, the Cochrane Database of Systematic Reviews, websites of regulatory authorities and registries of clinical trials, with no date or language restrictions, through September 2010 (updated March 2011) for published and unpublished studies. We selected double-blind randomized controlled trials of at least one week’s duration involving smokers or people who used smokeless tobacco that reported on cardiovascular events (ischemia, arrhythmia, congestive heart failure, sudden death or cardiovascular-related death) as serious adverse events asociated with the use of varenicline.

Results:

We analyzed data from 14 double-blind randomized controlled trials involving 8216 participants. The trials ranged in duration from 7 to 52 weeks. Varenicline was associated with a significantly increased risk of serious adverse cardiovascular events compared with placebo (1.06% [52/4908] in varenicline group v. 0.82% [27/3308] in placebo group; Peto odds ratio [OR] 1.72, 95% confidence interval [CI] 1.09–2.71; I² = 0%). The results of various sensitivity analyses were consistent with those of the main analysis, and a funnel plot showed no publication bias. There were too few deaths to allow meaningful comparisons of mortality.

Interpretation:

Our meta-analysis raises safety concerns about the potential for an increased risk of serious adverse cardiovascular events associated with the use of varenicline among tobacco users.Varenicline is one of the most widely used drugs for smoking cessation. It is a partial agonist at the α₄–β₂ nicotinic acetylcholine receptors and a full agonist at the α₇ nicotinic acetylcholine receptor.^1,2 The drug modulates parasympathetic output from the brainstem to the heart because of activities of the α₇ receptor.³ Acute nicotine administration can induce thrombosis.⁴ Possible mechanisms by which varenicline may be associated with cardiovascular disease might include the action of varenicline at the α₇ receptor in the brainstem or, similar to nicotine, a prothrombotic effect.^2–4At the time of its priority safety review of varenicline in 2006, the US Food and Drug Administration (FDA) noted that “[t]he serious adverse event data suggest that varenicline may possibly increase the risk of cardiac events, both ischemic and arrhythmic, particularly over longer treatment period.”⁵ Subsequently, the product label was updated: “Post marketing reports of myocardial infarction and cerebrovascular accidents including ischemic and hemorrhagic events have been reported in patients taking Chantix.”⁶ There are published reports of cardiac arrest associated with varenicline.⁷Cardiovascular disease is an important cause of morbidity and mortality among tobacco users. The long-term cardiovascular benefits of smoking cessation are well established.⁸ Although one statistically underpowered trial reported a trend toward excess cardiovascular events associated with the use of varenicline,⁹ a systematic review of information on the cardiovascular effects of varenicline is unavailable to clinicians.We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to ascertain the serious adverse cardiovascular effects of varenicline compared with placebo among tobacco users.     

The health risks of ART

Assisted reproductive technologies enable subfertile couples to have children. But there are health risks attached for both mothers and children that need to be properly understood and managed.Assisted reproductive technology (ART) has become a standard intervention for couples with infertility problems, especially as ART is highly successful and overall carries low risks [1,2]. The number of infants born following ART has increased steadily worldwide, with more than 5,000,000 so far [3]. In industrialized countries, 1–4% of newborns have been conceived by using ART [4,5], probably owing to the fact that couples frequently delay childbearing until their late 30s, when fertility decreases in both men and women [2]. Considering the possibility that male fertility might be declining, as Richard Sharpe has discussed in this series [6], it is likely that ART will be even more widely used in the future. Yet, as the rate of ART and the total number of pregnancies has increased, it has become apparent that ART is associated with potential risks to the mother and fetus. The most commonly cited health problems pertain to multiple gestation pregnancies and multiple births. More recently, however, concerns about the risks of birth defects and genetic disorders have been raised. There are questions about whether the required manipulations and the artificial environments of gametes and embryos are potentially creating short- and long-term health risks in mothers and children by interfering with epigenetic reprogramming.Notwithstanding, ART represents a tremendous achievement in human reproductive medicine. The birth of Louise Brown, the first ‘test tube baby'' in 1978, was the result of the collaborative work of embryologist Robert Edwards and gynaecologist Patrick Steptoe [7]. This success was a culmination of many years of work at universities and clinics worldwide. An initial lack of support, as well as criticism from ethicists and the church, delayed the opening of the first in vitro fertilization (IVF) clinic in Bourn Hall near Cambridge until 1980. By 1986, 1,000 children conceived by IVF at Bourn Hall had been born [8]. In 2010, Edwards received the Nobel Prize in Medicine for the development of IVF. Regrettably, Steptoe had passed away in 1988 and could not share the honour.…as the rate of ART and the total number of pregnancies has increased, it has become apparent that ART is associated with potential risks to mother and fetusOver the next decades, many improvements in IVF procedures were made to reduce the risks of adverse effects and increase success rates, including controlled ovarian stimulation, timed ovulation induction, ultrasound-guided egg retrieval, cryopreservation of embryos and intracytoplasmic sperm injection (ICSI)—a technique in which a single sperm cell is injected into an oocyte using a microneedle. In addition, there were further improvements such as assisted hatching and in media composition, such as sequential media, which allow the in vitro culture of the embryo to reach the blastocyst stage [8].Current IVF procedures involve multiple steps including ovarian stimulation and monitoring, oocyte retrieval from the ovary, fertilization in vitro and embryo transfer to the womb. Whereas the first IVF cycles, including the conception of Louise Brown, used natural ovulatory cycles, which result in the retrieval of one or two oocytes, most IVF cycles performed today rely on controlled ovarian stimulation using injectable gonadotropins—follicle stimulating hormone and luteinizing hormone—in supraphysiological concentrations for 10–14 days, followed by injection of human chorionic gonadotropin (hCG) 38–40 h before egg retrieval to trigger ovulation. This updated protocol makes it possible to grow multiple follicles and to retrieve 10–20 oocytes in one IVF cycle, thereby increasing the number of eggs available for fertilization.Post-retrieval, the embryologist places an egg and sperm together in a test tube for fertilization. Alternatively, a single sperm cell can be injected into an egg by using ICSI. This procedure was initially developed for couples with poor sperm quality [9], but has become the predominant fertilization technique used in many IVF clinics worldwide [8]. The developing embryos are monitored by microscopy, and viable embryos are transferred into the woman''s womb for implantation. Louise Brown, as with many embryos today, was transferred three days after egg retrieval, at approximately the eight-cell stage. However, using sequential media, many clinics advocate culturing embryos until day five when they reach the blastocyst stage. The prolonged culture period allows self-selection of the most viable embryos for transfer and increases the chance of a viable pregnancy. Excess embryos can be cryopreserved and transferred at a later date by using a procedure known as frozen embryo transfer (FET). In this article we use the term ART to refer to IVF procedures with or without ICSI and FET.

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.Embryos can also be screened for chromosomal aneuploidies—missing or extra chromosomes—by preimplantation genetic diagnosis (PGD) when indicated and when available. PGD can also be used to test fertile couples at increased risk of genetic disorders. To perform PGD, a single cell is obtained from three-day-old embryos for molecular testing, for example sequencing for inherited monogenic disorders or fluorescent in situ hybridization for chromosomal abnormalities [8]. Only embryos with a normal chromosomal constitution, and without the genetic disorder in question, would then be transferred into the woman''s womb.Despite tremendous progress during the past three decades, people undertaking ART still face a considerable risk of failure to achieve parenthood. The rate of clinical pregnancies in Bourn Hall between 1980 and 1985 was 24% and 14% in women younger and older than 40 years, respectively [10]. The reported rates for clinical pregnancies and live births vary by country; the average delivery rate is 22.4%, 23.3% and 17.1% for IVF, ICSI and FET cycles, respectively [11]. According to the last Centers for Disease Control and Prevention report in 2009, the average live-birth rate was 35% per fresh ART cycle, although it sharply declines with age, from 45% among women younger than 35 years to 7% among women older than 42 years [5]. The reasons include poor response to ovarian stimulation, ovarian hyperstimulation syndrome and failure of eggs to fertilize. However, these failures occur in only a minority of patients and the success rate of egg retrieval and fertilization leading to embryo transfer is a remarkable 90% [12].Implantation remains the least understood process and is a key rate-limiting step in ART. Poor embryo quality is considered to be the main cause of implantation failure and it reflects a high incidence of chromosomal aneuploidies, which increases with maternal age [13]. One obvious solution to improve implantation rates is to transfer more embryos. However, this also increases the risk of multiple births, and related morbidity and mortality in newborns. An alternative approach is to select for good-quality embryos by culturing them to the blastocyst stage, because it seems that aneuploid embryos arrest by this stage and that blactocysts are more likely to have a normal chromosomal complement. There is ongoing research aimed at identifying viable embryos through PGD and metabolic profiling [13].Despite tremendous progress during the past three decades, people undertaking ART still face a considerable risk of failure to achieve parenthoodIt has also been suggested that failure to implant could be caused by the inability of the embryo to hatch out of a glycoprotein layer surrounding the embryo, known as the ‘zona pellucida''; this layer hardens if the embryo is cultured or frozen. Assisted hatching by rupturing the zona pellucida before embryo transfer does increase clinical pregnancy rates, especially for thawed embryos [13]. Another factor linked to the failure of implantation is endometrial receptivity. The endometrium consists of multi-layered mucosa cells in the inner wall of the uterus, which undergoes coordinated remodelling during the menstrual cycle and there is a specific time window when it is receptive to embryo implantation. Several research studies have identified molecular biomarkers of poor endometrial receptivity, showing that prostaglandins, cell adhesion molecules, mucins and cytokines are important [13].When it comes to health risks for mothers and infants, the use of ART increases the risk of multiple births, including higher rates of caesarian sections, prematurity, low birth weight, infant death and disability. More recently, concerns regarding elevated risks of birth defects, genetic abnormalities, neurodevelopmental disorders and imprinting disorders have been reported; however, not all are substantiated. There are still many unanswered questions regarding the potential short- and long-term health risks of ART for women and children, and there are tremendous challenges in studying the safety of ART procedures. Apart from the subset of individuals undergoing ART for social reasons—single parents or same sex couples—most patients are subfertile couples. Subfertility, defined as a failure to conceive naturally after 12 months of unprotected intercourse, affects 8–20% of couples [2], and it can occur for a variety of unknown or known reasons including maternal factors—endocrine, hormonal, endometriosis and blocked fallopian tubes—and paternal factors such as spermatogenesis abnormalities.Most studies have assessed the risks of ART by comparing the outcomes of ART-conceived pregnancies to naturally conceived pregnancies. There is emerging evidence that underlying maternal or paternal subfertility might be an important factor in obstetric, neonatal and childhood outcomes in the ART population. Therefore, to determine the specific health risks associated with the ART process itself, the outcomes of ART-conceived pregnancies should be assessed in comparison with naturally conceived pregnancies in subfertile parents, which is methodologically difficult. Alternatively, studying the health risks of ART in fertile couples—for instance, same-sex couples and couples at risk of genetic disorders—would be informative, but the number of such couples is relatively small.Women who undergo ART are at risk of ovarian hyperstimulation syndrome (OHSS). OHSS is a complication of ovulation induction resulting in enlargement of ovaries and retention of fluids leading to various secondary complications, which normally resolve within two weeks, but can persist if pregnancy occurs. Patients with OHSS can be offered embryo cryopreservation and frozen embryo transfer when symptoms resolve. Moderate forms of OHSS occur in 5% of patients undergoing ART; 2% of patients require hospitalization. Death occurs with an incidence of approximately 3 per 100,000 ART cycles [14]. OHSS is predominantly caused by human chorionic gonadotropin injection used for inducing final oocyte maturation and ovulation. Research is focused on optimizing alternative stimulation protocols [14].The use of supraphysiological concentrations of hormones during ovarian stimulation has also raised concerns that ART can increase cancer risks linked to hormonal fluctuations. These include breast, ovarian, endometrial, cervical and colon cancers, as well as melanoma. Studies evaluating the risks of cervical cancers, colon cancers and melanoma have not demonstrated increased risks for women undergoing ART [1]. The data for breast, ovarian and endometrial cancer is more complex, however, and more research is required to conclusively determine whether there is an increased risk.The perinatal and obstetric risks of ART are most significantly influenced by multiple pregnancies. These are at a more than 60% risk of low birth weight or premature delivery [2], and related risks of pregnancy complications such as gestational diabetes, abnormal placentation and hypertensive disorders [1]. Multiple pregnancies occur in 1% of naturally conceived pregnancies and 25–50% of ART pregnancies, owing to multiple embryo transfer. In the Western world, about 30–50% of all twin pregnancies result from ART [2]. Whilst double or triple embryo transfer is still common, the development of cryopreservation techniques and extended blastocyst culture has increased the use of single embryo transfer (SET), especially for younger women. Many European countries and the province of Quebec, in Canada, where ART is publicly funded, have adopted a policy of SET, which has dramatically decreased the incidence of multiple pregnancies. In Belgium and Quebec, SET policies have reduced multiple pregnancies from 19% to 3% and from 27% to 6%, respectively. It has been argued that SET results in a lower live-birth rate than a double-embryo transfer, but this is almost completely overcome by an additional single frozen embryo cycle [2].…there are tremendous challenges in studying the safety of ART proceduresThe question of whether ART increases the risks of pregnancy complications, including prematurity and low birth weight in singletons, remains unresolved; several studies have found an increased risk, but others have not replicated these findings [1,2]. It has been suggested that the fertility history of patients undergoing ART is an important factor, as there is an association between the length of time to conception and prematurity and birth weight [15]. Prematurity and low birth weight are also known to be associated with long-term health effects, including adult onset coronary artery disease, hypertension, obesity and type 2 diabetes [16,17].Various studies have also reported a higher incidence of congenital anomalies in ART-conceived children, with a suggested 30% increase of malformations [2]. However, this is another risk that might be attributable to parental subfertility, as a study comparing children conceived by ART to subfertile parents and children conceived naturally to subfertile parents did not find any significant difference in the congenital anomaly rate [2]. Findings from another study of the risks of birth defects in children conceived naturally to women with and without a history of subfertility compared with children conceived with the assistance of ART also suggest that it is subfertility, rather than ART, that is associated with an increased risk of birth defects [18].Several studies reported an increased risk of cerebral palsy and other neurological abnormalities in children conceived by ART [2]. But again, these findings are mainly attributed to complications resulting from multiple pregnancies including prematurity and low birth weight. The increased utilization of SET is therefore expected to result in fewer multiple pregnancies, which should result in a concomitant decrease in neurological complications. Further evidence that neurological complications in ART children are not exclusively related to ART came from studies that have assessed neurodevelopmental outcomes, such as locomotion, cognition, language and behavioural development of ART children in comparison with naturally conceived children. These analyses did not reveal any differences when adjusted for confounding factors of low birth weight and prematurity. In a similar vein, numerous studies have investigated whether there is an increased incidence of autism in ART-conceived children, but these have been inconclusive [19].There are potential concerns regarding the fertility of ART children. However, this requires future studies as most of this population is younger than 30 years of age. There is some evidence that boys conceived through ICSI have an increased rate of genital anomalies [2] and that males with severe infertility, such as low sperm counts, are more likely to carry chromosomal abnormalities, which could be passed on to their children conceived through ICSI [15].It has also been suggested that there might be an increased risk of cancers in ART-conceived offspring. Although multiple studies have identified no such risk, a large Swedish study reported a marginally increased risk of cancer, including haematologic, eye, nervous system, solid tumours and histiocytosis [2]. Similarly to other ART-related adverse health outcomes, it has been suggested that the increased risk of cancer could be attributed to prematurity, a recognized risk factor for cancer, rather than to the ART procedure itself. Further long-term studies are required to determine if there is truly an increased risk of adult cancers in ART offspring.…there remain unanswered questions about both the health risks associated with ART and the potential mechanisms that could account for these findingsOne thing is clear from the available evidence to date: there remain unanswered questions about both the health risks associated with ART and the potential mechanisms that could account for these findings. One possible explanation is that the exposure of gametes and preimplantation embryos to the various steps of ART might affect growth and development of offspring through dysregulation of epigenetic pathways [20]. In addition, there is evidence that genetic and epigenetic alterations might be inherited from the gametes of subfertile parents, which would reinforce assertions that subfertility itself might play a role in ART-related health outcomes [1,20].Epigenetics refers to heritable changes in gene expression without alterations to the underlying DNA sequence. DNA methylation and modifications of histones are epigenetic modifications that determine active against repressive conformation of chromatin structure, thereby regulating gene expression and driving essential processes such as embryonic development, fetal organ development, cell differentiation and tissue-specific gene expression [21]. Genomic imprinting is a type of epigenetic gene regulation that uses epigenetic marks to silence specifically one of the parental alleles. There are approximately 100 known imprinted genes in humans [22]. Most imprinted genes are found in clusters across the genome and are regulated by parent-specific DNA methylation and histone modification marks at cis-acting imprinting centres, as well as non-coding RNAs. Most of the known imprinted genes have functions related to growth and behaviour; disruption of the normally programmed parental expression of imprinted genes can therefore result in disorders related to growth and neurodevelopment.Gametogenesis and embryogenesis are important stages of mammalian development that require genome-wide epigenetic reprogramming. During spermatogenesis, protamines replace most histone proteins to create a highly compacted DNA. Establishment of DNA methylation imprints at paternally methylated imprinting centres is complete in males at the time of birth. In females, the establishment of maternally methylated imprinting centres begins during puberty and is almost complete in ovulated oocytes. After fertilization, the paternal genome undergoes rapid active DNA demethylation in which protamines are replaced by histones, whilst the maternal genome is passively demethylated, so that DNA methylation patterns are lost through cell divisions. Although, the whole genome undergoes demethylation, parent-specific DNA methylation is maintained at imprinting centres. Subsequently, the genome is remethylated and cell-type-specific epigenetic patterns are established as embryonic development proceeds. The parent-specific DNA methylation at imprinting centres is maintained in somatic cells, but it is erased and re-established in the gametes starting a new cycle of imprinting (Fig 1; [23]). As the establishment and maintenance of imprinting marks coincides in timing with important stages of ART, such as oocyte maturation under supraphysiological hormone concentrations and embryo culture, it has been proposed that ART can lead to imprinting errors [24].Open in a separate windowFigure 1Life cycle of genomic imprinting and assisted reproductive technology. Erasure, re-establishment and maintenance of genomic imprinting occur during gametogenesis and preimplantation embryo development. Blue and red solid lines show paternal and maternal methylation at imprinting centres through gametogenesis and early stages of preimplantation development. Imprinting marks are erased at early stages of gametogenesis. Re-establishment of imprinting occurs throughout gametogenesis, but finishes much later in oocytes compared with sperm. During preimplantation development, both maternal and paternal imprinting marks are maintained whilst the rest of the genome is demethylated. The paternal genome is demethylated rapidly and actively (dashed blue line) whilst the maternal genome is demethylated at a slower rate passively through cell division (dashed red line). Various steps of assisted reproductive technology such as ovarian stimulation, ovulation induction, gamete and embryo manipulation and culturing create unusual environments for gametes and embryos and thus, can interfere with proper establishment of imprinting marks in oocytes or maintenance of imprinting marks in embryos. Subfertility can be associated with epigenetic errors in imprinting erasure and/or establishment in both oocytes and sperm. Adapted from [23].In 2001, the first evidence that genomic imprinting can be perturbed during ART procedures came from studying sheep fetuses derived from in vitro cultured embryos that presented with large offspring syndrome (LOS; [25]). LOS occurs sporadically in cattle and sheep conceived by IVF and is characterized by a 20–30% increase in birth weight frequently accompanied by congenital anomalies and placental dysfunction [24]. Owing to phenotypic similarities of LOS to the human overgrowth disorder Beckwith–Wiedemann syndrome (BWS), which is caused by the dysregulation of gene expression within an imprinted cluster on chromosome 11p15.5, the authors hypothesized that genes from the orthologous cluster in sheep or a closely related pathway could be dysregulated in LOS. They tested expression of the insulin-like growth factor 2 (IGF2) gene known to be overexpressed in BWS, and the IGF2R receptor gene, which is involved in clearance of IGF2 from the circulation. IGF2R is imprinted in sheep but not in humans. In sheep with LOS, no differences for IGF2 were found, but reduced expression of IGF2R was observed after loss of DNA methylation at the imprinting centre for this gene [25].In the following decade, several studies provided further evidence that children conceived by ART might be at increased risk of imprinting disorders. The strongest case has been made for BWS and Angelman syndrome. BWS is the most common human overgrowth syndrome characterized by prenatal and postnatal overgrowth, congenital anomalies and tumour predisposition [26]. Angelman syndrome is a neurodevelopmental disorder characterized by microcephaly, severe intellectual disability and a unique behavioural profile including frequent laughter, smiling and excitability [27]. Multiple case reports from various countries indicate an increased frequency of BWS and Angelman syndrome in ART children (3–10-fold) compared with the general population. However, two cohort studies failed to replicate this association [28]. The low incidence of both BWS (1 in 13,700) and Angelman syndrome (1 in 15,000) in the general population [28] makes epidemiological studies difficult—the two cohort studies reported 2,492 and 6,052 ART children, respectively, and are probably underpowered to detect an increased risk of BWS and Angelman syndrome. However, even if there might be increased relative risks for these syndromes in ART children, the absolute risks in this population remain low.The molecular causes of BWS and Angelman syndrome are heterogeneous. They include genomic (deletion, uniparental disomy and gene mutation) and epigenetic (loss of imprinting due to aberrant DNA methylation) alterations at imprinted gene clusters on chromosomes 11p5.5 and 15q11–q13, respectively. These alterations occur with specific frequencies for each of the two disorders [26,27]. Results of molecular testing in children with these syndromes and conceived using ART, reveal an excess of epigenetic compared with genetic molecular alterations. For example, loss of DNA methylation at imprinting centre 2 occurs in about 50% of BWS cases in the general population, whereas several studies found loss of DNA methylation at imprinting centre 2 in 96% (27/28) of BWS ART-conceived children. In Angelman syndrome, approximately 3% of cases in the general population have loss of methylation at 15q11–13, whereas 5 out of 19 (26%) Angelman syndrome children conceived by ART or naturally by parents with a history of subfertility had loss of DNA methylation at 15q11–13 (Fig 2).Open in a separate windowFigure 2Enrichment of epigenetic alterations in Beckwith–Wiedemann syndrome and Angelman syndrome after assisted reproductive technology. Loss of methylation (LOM) at imprinting centre 2 (IC2) on chromosome 11p15.5 contributes to 50% of Beckwith–Wiedemann syndrome (BWS) cases in the general population, whereas LOM at IC2 is found in 27 out of 28 cases (96%) in the BWS assisted reproductive technology (ART) population, which represents a 1.9-fold enrichment of this epigenetic defect. For Angelman syndrome (AS), methylation disruption at the 15q11–q13 imprinting centre contributes to 3% of AS cases, and in the AS ART and subfertility population it was found in 5 out of 19 cases (26%; eight fold enrichment). Data from the following publications were used for these calculations, BWS [31,32,33,34,35] AS [35,36].The data for loss of DNA methylation in Angelman syndrome cases conceived naturally by subfertile parents highlights the fact that epigenetic alterations could, at least in part, result from underlying parental subfertility. Indeed, several studies have shown that abnormalities of spermatogenesis, such as oligospermia (low sperm concentration), low sperm motility or abnormal sperm morphology are associated with altered DNA methylation at imprinted loci. These occur in both maternal and paternal alleles of imprinting centres in sperm and could be transmitted to offspring conceived by ART [26]. One study of chromosomally normal fetuses spontaneously aborted at six to nine weeks of gestation found that DNA methylation alterations at imprinted loci were sometimes inherited from sperm. Thus, it is possible that this dysregulation of imprinting in male gametes might be one cause of the association between imprinting disorders and ART.Studies of other known imprinted syndromes, such as Prader–Willi syndrome, Russell–Silver syndrome, maternal and paternal uniparental disomy of chromosome 14, pseudohypoparathyroidism type 1b and transient neonatal diabetes mellitus, have either not demonstrated an association with ART or have been inconclusive owing to their small size [29]. A link has also been suggested between ART and the newly defined ‘multiple maternal hypomethylation syndrome'', which clinically presents either as BWS or transient neonatal diabetes mellitus, and is associated with loss of DNA methylation at multiple maternally methylated imprinting centres; loss of methylation at paternal imprinting centres has not been reported so far. Thus, human imprinting disorders that have been observed with increased relative frequency in ART offspring are confined to loss of DNA methylation at maternally methylated imprinting centres, similar to epimutations of IGF2R in LOS. One could propose that ART has a greater impact on female than male gametes, as the eggs are subjected to more environmental exposures—supraphysiological doses of hormones—and more manipulation than the sperm. However, studies of mouse in vitro cultured embryos and ART-exposed human and mouse gametes suggest that ART can also be associated with either loss or gain of DNA methylation on both maternal and paternal alleles [23].Mouse models are a valuable method to investigate which stages of ART procedures can disrupt normal imprinting patterns. The advantage of using mouse models is the ability to investigate each of the parameters of ART—ovulation stimulation and embryo culturing—separately and at different stages of development. Furthermore, mouse models allow investigators to alter ART parameters, such as concentration of hormones or media for embryo culturing. Most importantly, studies in animal models have shown that ART procedures without the confounding factor of subfertility do have a negative impact on imprint regulation [23].The exposure of maturing oocytes from mice to abnormally high doses of gonadotropins has been suggested to alter imprint establishment. Yet, studies performed directly on superovulated oocytes are inconclusive, as not all of them have demonstrated increased rates of DNA methylation errors at imprint centres compared with spontaneously ovulated oocytes. Interestingly, studies of DNA methylation in mouse blastocysts harvested from superovulated mothers identified an increased rate of DNA methylation errors at imprint centres. This included loss of DNA methylation at the paternally methylated H19—the imprinting centre on human chromosome 11 and mouse chromosome 7 implicated in BWS and the related undergrowth Russell–Silver syndrome. It suggests that superovulation also impairs imprinting maintenance; probably by affecting the ability of the oocyte to synthesize and store sufficient maternal factors (RNA and proteins; [23]). In support of this hypothesis, four maternal effect proteins have been previously identified that are involved in imprinting maintenance in preimplantation embryos. It was also found that imprint errors arise in blastocysts in a dose-dependent manner—higher doses of hormones resulted in DNA methylation errors in a larger number of embryos [23].As the establishment and maintenance of imprinting marks coincides in timing with important stages of ART […] it has been proposed that ART can lead to imprinting errorsAnother factor that might contribute to imprinting errors is the micromanipulation of gametes during IVF and ICSI procedures. Evidence supporting this hypothesis includes the observation in mouse models that a higher number of IVF embryos—resulting from superovulation alone or superovulation and embryo culturing—have aberrant H19 DNA methylation compared with in vivo conceived embryos [23]. Media with varying compositions are used in ART clinics, and whilst all of the media are suboptimal for normal maintenance of all DNA imprints in mouse embryos, the number of embryos with aberrant DNA methylation at imprinting centres varies depending on the media [23]. Interestingly, it was also found that embryos with faster rates of development are more prone to loss of DNA methylation at imprinting centres [23].Though it is not yet clear how these findings relate to ART in humans, the mouse research is crucial for informing human studies about which variables should be addressed to optimize the safety and efficacy of ART procedures. Apart from ART itself, it has been shown that compromised fertility in mice results in loss or delay of DNA methylation acquisition in one of three tested imprinted genes. The compromised fertility is induced by genetic manipulation of a gene involved in communication between oocytes and surrounding follicular cells, which is crucial for proper oocyte maturation. The results suggest that the observed loss of DNA methylation could be caused by impaired transport of metabolites from follicular cells to oocytes, which is important for imprint establishment [23].Data linking dysregulation of imprinted loci and ART is limited to several imprinted gene clusters associated with clinically recognizable syndromes. However, there are more genes in the human genome that have been discovered to be, or are predicted to be, imprinted [22] but are not yet known to be associated with clinical phenotypes. Potentially, ART can lead to dysregulation of these imprinted genes, which might be another, as yet unrecognized factor contributing to neonatal and long-term health problems of ART-conceived children. At this point, it is also not clear whether epigenetic disruption during ART is limited to imprinted genes or has more global effects on the genome. The data for genome-wide DNA methylation analysis are limited in both human and mouse to individuals with no apparent disease phenotype. So far, these data have been inconclusive [23,28].One could propose that ART has a greater impact on female than male gametes, as the eggs are subjected to more environmental exposures […] and more manipulation than the spermDespite significant advances in the efficacy and success of ART procedures during the past few decades, the health risks, especially related to long-term outcomes in ART-conceived children, remain poorly understood. Moreover, the phenomena known as ‘fetal programming''—when maternal and in utero exposures can lead to various adult onset disease susceptibilities—have been suggested to be transmissible to the next generations, probably through epigenetic mechanisms [30]. In the case of ART procedures, the effect of ‘unusual'' environments during gametogenesis and early embryonic development on adult-onset disease and trans-generational inheritance is still not clear. Additional research is needed to elucidate the effects of ART on genome-wide epigenetic patterns and their link to human disease. As ART will continue to be an important medical intervention and the number of children born with the help of ART procedures will probably continue to rise in the future, it is crucial to understand the associated health risks and underlying molecular mechanisms of these technologies. This will increase the safety of this intervention and enable couples using ART to be fully informed regarding both present and future health-related risks.? Open in a separate windowDaria GrafodatskayaOpen in a separate windowCheryl CytrynbaumOpen in a separate windowRosanna Weksberg     

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.     

A qualitative investigation of smoke-free policies on hospital property

Background:

Many hospitals have adopted smoke-free policies on their property. We examined the consequences of such polices at two Canadian tertiary acute-care hospitals.

Methods:

We conducted a qualitative study using ethnographic techniques over a six-month period. Participants (n = 186) shared their perspectives on and experiences with tobacco dependence and managing the use of tobacco, as well as their impressions of the smoke-free policy. We interviewed inpatients individually from eight wards (n = 82), key policy-makers (n = 9) and support staff (n = 14) and held 16 focus groups with health care providers and ward staff (n = 81). We also reviewed ward documents relating to tobacco dependence and looked at smoking-related activities on hospital property.

Results:

Noncompliance with the policy and exposure to secondhand smoke were ongoing concerns. Peoples’ impressions of the use of tobacco varied, including divergent opinions as to whether such use was a bad habit or an addiction. Treatment for tobacco dependence and the management of symptoms of withdrawal were offered inconsistently. Participants voiced concerns over patient safety and leaving the ward to smoke.

Interpretation:

Policies mandating smoke-free hospital property have important consequences beyond noncompliance, including concerns over patient safety and disruptions to care. Without adequately available and accessible support for withdrawal from tobacco, patients will continue to face personal risk when they leave hospital property to smoke.Canadian cities and provinces have passed smoking bans with the goal of reducing people’s exposure to secondhand smoke in workplaces, public spaces and on the property adjacent to public buildings.^1,2 In response, Canadian health authorities and hospitals began implementing policies mandating smoke-free hospital property, with the goals of reducing the exposure of workers, patients and visitors to tobacco smoke while delivering a public health message about the dangers of smoking.^2–5 An additional anticipated outcome was the reduced use of tobacco among patients and staff. The impetuses for adopting smoke-free policies include public support for such legislation and the potential for litigation for exposure to second-hand smoke.^2,4Tobacco use is a modifiable risk factor associated with a variety of cancers, cardiovascular diseases and respiratory conditions.^6–11 Patients in hospital who use tobacco tend to have more surgical complications and exacerbations of acute and chronic health conditions than patients who do not use tobacco.^6–11 Any policy aimed at reducing exposure to tobacco in hospitals is well supported by evidence, as is the integration of interventions targetting tobacco dependence.¹² Unfortunately, most of the nearly five million Canadians who smoke will receive suboptimal treatment,¹³ as the routine provision of interventions for tobacco dependence in hospital settings is not a practice norm.^14–16 In smoke-free hospitals, two studies suggest minimal support is offered for withdrawal, ^17,18 and one reports an increased use of nicotine-replacement therapy after the implementation of the smoke-free policy.¹⁹Assessments of the effectiveness of smoke-free policies for hospital property tend to focus on noncompliance and related issues of enforcement.^17,20,21 Although evidence of noncompliance and litter on hospital property^2,17,20 implies ongoing exposure to tobacco smoke, half of the participating hospital sites in one study reported less exposure to tobacco smoke within hospital buildings and on the property.¹⁸ In addition, there is evidence to suggest some decline in smoking among staff.^18,19,21,22We sought to determine the consequences of policies mandating smoke-free hospital property in two Canadian acute-care hospitals by eliciting lived experiences of the people faced with enacting the policies: patients and health care providers. In addition, we elicited stories from hospital support staff and administrators regarding the policies.     

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.     

Higher risk of venous thrombosis associated with drospirenone-containing oral contraceptives: a population-based cohort study

Background:

Combined oral contraceptives are a common method of contraception, but they carry a risk of venous and arterial thrombosis. We assessed whether use of drospirenone was associated with an increase in thrombotic risk relative to third-generation combined oral contraceptives.

Methods:

Using computerized records of the largest health care provider in Israel, we identified all women aged 12 to 50 years for whom combined oral contraceptives had been dispensed between Jan. 1, 2002, and Dec. 31, 2008. We followed the cohort until 2009. We used Poisson regression models to estimate the crude and adjusted rate ratios for risk factors for venous thrombotic events (specifically deep vein thrombosis and pulmonary embolism) and arterial thromboic events (specifically transient ischemic attack and cerebrovascular accident). We performed multivariable analyses to compare types of contraceptives, with adjustment for the various risk factors.

Results:

We identified a total of 1017 (0.24%) venous and arterial thrombotic events among 431 223 use episodes during 819 749 woman-years of follow-up (6.33 venous events and 6.10 arterial events per 10 000 woman-years). In a multivariable model, use of drospirenone carried an increased risk of venous thrombotic events, relative to both third-generation combined oral contraceptives (rate ratio [RR] 1.43, 95% confidence interval [CI] 1.15–1.78) and second-generation combined oral contraceptives (RR 1.65, 95% CI 1.02–2.65). There was no increase in the risk of arterial thrombosis with drospirenone.

Interpretation:

Use of drospirenone-containing oral contraceptives was associated with an increased risk of deep vein thrombosis and pulmonary embolism, but not transient ischemic attack or cerebrovascular attack, relative to second- and third-generation combined oral contraceptives.Oral hormonal therapy is the preferred method of contraception, especially among young women. In the United States in 2002, 12 million women were using “the pill.”¹ In a survey of households in Great Britain conducted in 2005 and 2006, one-quarter of women aged 16 to 49 years of age were using this form of contraception.² A large variety of combined oral contraceptive preparations are available, differing in terms of estrogen dose and in terms of the dose and type of the progestin component. Among preparations currently in use, the estrogen dose ranges from 15 to 35 μg, and the progestins are second-generation, third-generation or newer. The second-generation progestins (levonorgestrel and norgestrel), which are derivatives of testosterone, have differing degrees of androgenic and estrogenic activities. The structure of these agents was modified to reduce the androgenic activity, thus producing the third-generation progestins (desogestrel, gestodene and norgestimate). Newer progestins are chlormadinone acetate, a derivative of progesterone, and drospirenone, an analogue of the aldosterone antagonist spironolactone having antimineralo-corticoid and antiandrogenic activities. Drospirenone is promoted as causing less weight gain and edema than other forms of oral contraceptives, but few well-designed studies have compared the minor adverse effects of these drugs.³The use of oral contraceptives has been reported to confer an increased risk of venous and arterial thrombotic events,^4–7 specifically an absolute risk of venous thrombosis of 6.29 per 10 000 woman-years, compared with 3.01 per 10 000 woman-years among nonusers.⁸ It has long been accepted that there is a dose–response relationship between estrogen and the risk of venous thrombotic events. Reducing the estrogen dose from 50 μg to 20–30 μg has reduced the risk.⁹ Studies published since the mid-1990s have suggested a greater risk of venous thrombotic events with third-generation oral contraceptives than with second-generation formulations,^10–13 indicating that the risk is also progestin-dependent. The pathophysiological mechanism of the risk with different progestins is unknown. A twofold increase in the risk of arterial events (specifically ischemic stroke^6,14 and myocardial infarction⁷) has been observed in case–control studies for users of second-generation pills and possibly also third-generation preparations.^7,14Conflicting information is available regarding the risk of venous and arterial thrombotic events associated with drospirenone. An increased risk of venous thromboembolism, relative to second-generation pills, has been reported recently,^8,15,16 whereas two manufacturer-sponsored studies claimed no increase in risk.^17,18 In the study reported here, we investigated the risk of venous and arterial thrombotic events among users of various oral contraceptives in a large population-based cohort.     

Autophagy--alias self-eating--appetite and ageing

Two articles—one published online in January and in the March issue EMBO reports—implicate autophagy in the control of appetite by regulating neuropeptide production in hypothalamic neurons. Autophagy decline with age in POMC neurons induces obesity and metabolic syndrome.Kaushik et al. EMBO reports, this issue doi:10.1038/embor.2011.260Macroautophagy, which I will call autophagy, is a critical process that degrades bulk cytoplasm, including organelles, protein oligomers and a range of selective substrates. It has been linked with diverse physiological and disease-associated functions, including the removal of certain bacteria, protein oligomers associated with neurodegenerative diseases and dysfunctional mitochondria [1]. However, the primordial role of autophagy—conserved from yeast to mammals—appears to be its ability to provide nutrients to starving cells by releasing building blocks, such as amino acids and free fatty acids, obtained from macromolecular degradation. In yeast, autophagy deficiency enhances death in starvation conditions [2], and in mice it causes death from starvation in the early neonatal period [3,4]. Two recent articles from the Singh group—one of them in this issue of EMBO reports—also implicate autophagy in central appetite regulation [5,6].Autophagy seems to decline with age in the liver [7], and it has thus been assumed that autophagy declines with age in all tissues, but this has not been tested rigorously in organs such as the brain. Conversely, specific autophagy upregulation in Caenorhabditis elegans and Drosophila extends lifespan, and drugs that induce autophagy—but also perturb unrelated processes, such as rapamycin—promote longevity in rodents [8].Autophagy literally means self-eating, and it is therefore interesting to see that this cellular ‘self-eating'' has systemic roles in mammalian appetite control. The control of appetite is influenced by central regulators, including various hormones and neurotransmitters, and peripheral regulators, including hormones, glucose and free fatty acids [9]. Autophagy probably has peripheral roles in appetite and energy balance, as it regulates lipolysis and free fatty acid release [10]. Furthermore, Singh and colleagues have recently implicated autophagy in central appetite regulation [5,6].The arcuate nucleus in the hypothalamus has received extensive attention as an integrator and regulator of energy homeostasis and appetite. Through its proximity to the median eminence, which is characterized by an incomplete blood–brain barrier, these neurons rapidly sense metabolic fluctuations in the blood. There are two different neuronal populations in the arcuate nucleus, which appear to have complementary effects on appetite (Fig 1). The proopiomelanocortin (POMC) neurons produce the neuropeptide precursor POMC, which is cleaved to form α-melanocyte stimulating hormone (α-MSH), among several other products. The α-MSH secreted from these neurons activates melanocortin 4 receptors on target neurons in the paraventricular nucleus of the hypothalamus, which ultimately reduce food intake. The second group of neurons contain neuropeptide Y (NPY) and Agouti-related peptide (AgRP). Secreted NPY binds to downstream neuronal receptors and stimulates appetite. AgRP blocks the ability of α-MSH to activate melanocortin 4 receptors [11]. Furthermore, AgRP neurons inhibit POMC neurons [9].Open in a separate windowFigure 1Schematic diagram illustrating the complementary roles of POMC and NPY/AgRP neurons in appetite control. AgRP, Agouti-related peptide; MC4R, melanocortin 4 receptor; α-MSH, α-melanocyte stimulating hormone; NPY, neuropeptide Y; POMC, proopiomelanocortin.The first study from Singh''s group started by showing that starvation induces autophagy in the hypothalamus [5]. This finding alone merits some comment. Autophagy is frequently assessed by using phosphatidylethanolamine-conjugated Atg8/LC3 (LC3-II), which is specifically associated with autophagosomes and autolysosomes. LC3-II levels on western blot and the number of LC3-positive vesicles strongly correlate with the number of autophagosomes [1]. To assess whether LC3-II formation is altered by a perturbation, its level can be assessed in the presence of lysosomal inhibitors, which inhibit LC3-II degradation by blocking autophagosome–lysosome fusion [12]. Therefore, differences in LC3-II levels in response to a particular perturbation in the presence of lysosomal inhibitors reflect changes in autophagosome synthesis. An earlier study using GFP-LC3 suggested that autophagy was not upregulated in the brains of starved mice, compared with other tissues where this did occur [13]. However, this study only measured steady state levels of autophagosomes and was performed before the need for lysosomal inhibitors was appreciated. Subsequent work has shown rapid flux of autophagosomes to lysosomes in primary neurons, which might confound analyses without lysosomal inhibitors [14]. Thus, the data of the Singh group—showing that autophagy is upregulated in the brain by a range of methods including lysosomal inhibitors [5]—address an important issue in the field and corroborate another recent study that examined this question by using sophisticated imaging methods [15].“…decreasing autophagy with ageing in POMC neurons could contribute to the metabolic problems associated with age”Singh and colleagues then analysed mice that have a specific knockout of the autophagy gene Atg7 in AgRP neurons [5]. Although fasting increases AgRP mRNA and protein levels in normal mice, these changes were not seen in the knockout mice. AgRP neurons provide inhibitory signals to POMC neurons, and Kaushik and colleagues found that the AgRP-specific Atg7 knockout mice had higher levels of POMC and α-MSH, compared with the normal mice. This indicated that starvation regulates appetite in a manner that is partly dependent on autophagy. The authors suggested that the peripheral free fatty acids released during starvation induce autophagy by activating AMP-activated protein kinase (AMPK), a known positive regulator of autophagy. This, in turn, enhances degradation of hypothalamic lipids and increases endogenous intracellular free fatty acid concentrations. The increased intracellular free fatty acids upregulate AgRP mRNA and protein expression. As AgRP normally inhibits POMC/α-MSH production in target neurons, a defect in AgRP responses in the autophagy-null AgRP neurons results in higher α-MSH levels, which could account for the decreased mouse bodyweight.In follow-up work, Singh''s group have now studied the effects of inhibiting autophagy in POMC neurons, again using Atg7 deletion [6]. These mice, in contrast to the AgRP autophagy knockouts, are obese. This might be accounted for, in part, by an increase in POMC preprotein levels and its cleavage product adrenocorticotropic hormone in the knockout POMC neurons, which is associated with a failure to generate α-MSH. Interestingly, these POMC autophagy knockout mice have impaired peripheral lipolysis in response to starvation, which the authors suggest might be due to reduced central sympathetic tone to the periphery from the POMC neurons. In addition, POMC-neuron-specific Atg7 knockout mice have impaired glucose tolerance.This new study raises several interesting issues. How does the autophagy defect in the POMC neurons alter the cleavage pattern of POMC? Is this modulated within the physiological range of autophagy activity fluctuations in response to diet and starvation? Importantly, in vivo, autophagy might fluctuate similarly (or possibly differently) in POMC and AgRP neurons in response to diet and/or starvation. Given the tight interrelation of these neurons, how does this affect their overall response to appetite regulation in wild-type animals?Finally, the study also shows that hypothalamic autophagosome formation is decreased in older mice. To my knowledge, this is the first such demonstration of this phenomenon in the brain. The older mice phenocopied aspects of the POMC-neuron autophagy null mice—increased hypothalamic POMC preprotein and ACTH and decreased α-MSH, along with similar adiposity and lipolytic defects, compared with young mice. These data are provocative from several perspectives. In the context of metabolism, it is tantalizing to consider that decreasing autophagy with ageing in POMC neurons could contribute to the metabolic problems associated with ageing. Again, this model considers the POMC neurons in isolation, and it would be important to understand how reduced autophagy in aged AgRP neurons counterbalances this situation. In a more general sense, the data strongly support the concept that neuronal autophagy might decline with age.Autophagy is a major clearance route for many mutant, aggregate-prone intracytoplasmic proteins that cause neurodegenerative disease, such as tau (Alzheimer disease), α-synuclein (Parkinson disease), and huntingtin (Huntington disease), and the risk of these diseases is age-dependent [1]. Thus, it is tempting to suggest that the dramatic age-related risks for these diseases could be largely due to decreased neuronal capacity of degrading these toxic proteins. Neurodegenerative pathology and age-related metabolic abonormalities might be related—some of the metabolic disturbances that occur in humans with age could be due to the accumulation of such toxic proteins. High levels of these proteins are seen in many people who do not have, or who have not yet developed, neurodegenerative diseases, as many of them start to accumulate decades before any sign of disease. These proteins might alter metabolism and appetite either directly by affecting target neurons, or by influencing hormonal and neurotransmitter inputs into such neurons.