pRb or its cousins: Who controls the family business?

Comment on: Bazarov A, et al. Cell Cycle 2012; 11:1008–1013More than 90% of human cancers are of epithelial origin. Cellular senescence of human mammary epithelial cells (HMECs) is an important barrier that protects cells from immortalization; the first step in breast cancer development.¹ Although induction of tumor suppressor p16 is not evident in some types of normal human fibroblasts undergoing senescence,² in cultured HMECs, senescence occurs by a robust p16 induction, and cells that acquire silencing of p16Ink4a locus eventually proliferate and undergo senescence again by telomere shortening in a p53-dependent manner.¹ Therefore, p16 induction is a critical barrier to immortalize HMECs in culture. p16 inhibits kinase activity of Cdk4/6-cyclinD complexes, which inactivate three pRb family proteins: pRb, p107 and p130. However, the relative contribution of these three pRb family proteins to HMEC senescence is not well understood.In a recent issue of Cell Cycle, Bazarov et al. examined the role of each pRb family protein in p16-mediated senescence in breast cancer cell lines and in HMECs (Fig. 1).³ They showed that knockdown of each of the three pRb family proteins individually did not abrogate senescence mediated by ectopically expressed p16 in the breast cancer cell lines MDA-MB-231 and MCF7. However, the senescence induced by ectopic p16 was abrogated if they introduced E7, which inactivates all three pRb family proteins. Their data suggest that two of pRb family proteins can compensate for the loss of each pRb family protein to induce p16-mediated senescence in these cancer cells. The remaining question is whether all three pRb family members play an additive role, and whether the inactivation of at least two members of the pRb family is required to overcome p16-induced senescence in breast cancer cells. On the other hand, they showed that abrogation of pRb, but not of p107 and/ or p130, attenuates senescence in HMECs, suggesting a non-redundant critical role of pRb in HMEC senescence. These data are consistent with a recent report demonstrating that pRb has a non-redundant role in repressing DNA replication during H-ras-induced senescence of human fibroblasts,⁴ and explain why pRb, but not p107 or p130, is frequently mutated in cancer. Interestingly, although abrogation of pRb is critical for HMECs escaping senescence, simultaneous depletion of pRb together with either p107, p130 or both accelerates bypass of senescence. This suggests that p107 and p130 help pRb to trigger/maintain HMEC senescence in culture and possibly in vivo. Although each pRb family protein preferentially binds to different members of the E2F family,⁵ the contribution of each E2F family protein in escaping p16-mediated senescence remains unclear. Therefore, it will be interesting to see whether the critical role of pRb, and a supportive role of p130 and p107, in p16-mediated HMEC senescence depend on how each pRb family protein interacts with an E2F family protein.Open in a separate windowFigure 1. Contribution of pRb family proteins to p16-mediated senescence in breast cancer cells and HMECs. Knockdown of each of the three pRb family proteins in breast cancer cells does not abrogate ectopic p16-induced senescence, suggesting that either two of pRb family proteins can compensate for the loss of each pRb family proteins or all three of pRb family proteins play an additive role in p16-mediated senescence in breast cancer cells. On the other hand, knockdown of pRb, but not of p107 or p130, abrogates HMEC senescence, suggesting a non-redundant critical role for pRb in senescence of HMECs. However, the knockdown of either p107 or p130, in conjunction with pRb depletion, abrogates HMEC senescence more efficiently than pRb knockdown alone. This suggests a supporting role for p107 and p130 in maintaining HMEC senescence.Bazarov et al. also showed that even aggressive p53-negative breast cancer cells undergo cellular senescence upon ectopic p16 expression. These results are quite encouraging from an epigenetic therapy point of view. Silencing of p16 often occurs in breast cancer cells via promoter methylation. During DNA replication, cells require new p16 promoter methylation to keep p16 silenced. The observations of Bazarov et al. suggest that we may be able to stop the growth of even aggressive p53-negative breast cancers in patients by inducing p16 expression in cancer cells using DNA methylation inhibitors. Back to the question of running family business: “it appears that pRb is still the boss, but in some cases, it may get a helping hand from his cousins- p107 and p130.”     

Autophagy and EMT in cancer and metastasis: Who controls whom?

Metastasis consists of hallmark events, including Epithelial-Mesenchymal Transition (EMT), angiogenesis, initiation of inflammatory tumor microenvironment, and malfunctions in apoptosis. Autophagy is known to play a pivotal role in the metastatic process. Autophagy has pulled researchers towards it in recent times because of its dual role in the maintenance of cancer cells. Evidence states that cells undergoing EMT need autophagy in order to survive during migration and dissemination. Additionally, it orchestrates EMT markers in certain cancers. On the other side of the coin, autophagy plays an oncosuppressive role in impeding early metastasis. This review aims to project the interrelationship between autophagy and EMT. Targeting EMT via autophagy as a useful strategy is discussed in this review. Furthermore, for the first time, we have covered the possible reciprocating roles of EMT and autophagy and its consequences in cancer metastasis.     

Who needs a greener revolution?

Achieving food security for the future pits production increase against growth controlHow do we feed the nine billion people who are projected to inhabit the Earth by 2050? The issue is one of serious concern (Ash et al, 2010; Butler, 2010), as an increase in food production of up to 40% will be needed to cope with the growing population. In response, many scientists, politicians and economists have proposed a second ‘green revolution''. Their call references the first green revolution of the mid-twentieth century, which allowed many developing countries to drastically increase their food production. According to proponents of a new ‘global greener revolution'' (GGR), it will require an extensive transformation of agriculture to increase production and improve quality in an equitable and sustainable manner without compromising the environment (Godfray et al, 2010). Science and technology will be fundamental to achieving the goals of enhancing crop efficiency and food quality, as well as developing new protein sources (Beddington, 2010).…further analysis reveals that a GGR is not as charitable as it first appears; in fact, it could lead to undesired and even disastrous consequencesAt a glance, such a philanthropic proposal might seem the right thing to do, but further analysis reveals that a GGR is not as charitable as it first appears; in fact, it could lead to undesired and even disastrous consequences. This essay is therefore intended as a warning to scientists to think critically before signing up to a GRR: consider carefully the political, social and economic forces that would benefit from such a revolution and the potential long-term consequences for the environment and mankind.In an article for the Philosophical Transactions of the Royal Society, Sir John Beddington, the UK Government''s chief scientific adviser and professor of applied population biology at Imperial College London, lists the four main challenges for humanity in the twenty-first century as follows: to feed nine billion people in a sustainable way; to cope with increasing demands for clean water; to generate more energy; and to do all of this while mitigating and adapting to climate change (Beddington, 2010). Science will play a crucial role in this endeavour, provided the necessary investments are being made.The kinds of advances in science that the world requires are far reaching and various. Plant science will need to improve existing crops by breeding or genetic modification to increase photosynthetic efficiency, reduce the need for fertilizers, and develop new methods of pest, disease and weed control. Agricultural science and farmers need to develop sustainable livestock farming that reduces the emission of greenhouse gases, notably methane. Fisheries and aquaculture—high priorities for future food security—will require scientific knowledge and technological innovations to avoid over-fishing, to increase productivity and to deal with climate change and ocean acidification. Engineers will need to develop tools such as global positioning system-based fertilizing or watering systems and remote sensors to optimize the use of resources in agriculture. Nanotechnologies, genomics and electronics can be useful for improving disease diagnostics, the delivery of pesticides, fertilizers and water, or for monitoring and managing soil quality. Finally, science will also play a role in changing our diet to reduce the consumption of meat and dairy products and to develop alternative protein sources (The Royal Society, 2009; Beddington, 2010; Godfray et al, 2010).…the whole planet could turn into one giant farm for producing food and biofuels, with little or no wilderness leftTogether, these goals aim to achieve so-called sustainable intensification: producing more food from a given area while reducing the environmental impact (Godfray et al, 2010). This is a considerable challenge, resting on the hope that ‘greener'' innovations—mostly based on molecular biology and genetic manipulations of plants and farm animals—will be environmentally safer, although this is not a straightforward path in many cases.Scale matters in this endeavour, in terms of both space and time. Concerning space, the amount of land and sea surface needed to produce food for nine billion people will obviously be much larger than at present, any scientific progress notwithstanding. As such, given time, the whole planet could turn into one giant farm for producing food and biofuels, with little or no wilderness left. For defenders of the ownership approach (Bruce, 2008), for whom the Earth is ours to be exploited at our convenience, this vision might not be disturbing; nevertheless, the consequences would be catastrophic, not least because this approach gives no consideration to a sustainable future beyond this century. It is important to bear in mind that the GGR is proposed as a means to cope with human population growth during the next 40 years only. This might seem a long-term view from today''s perspective (Godfray et al, 2010), but it barely considers even the next two generations. A true long-term view needs to embrace a far more extended timeframe and consider our great-grandchildren and the world they might live in.If a GGR were a resounding success, most humans living beyond 2050 would be fed and healthy, but they would inherit a planetary farm with little wilderness and biodiversity. This, together with the possibility of notably extending life expectancy (Lucke et al, 2010) and the conviction that the next GGR will be always possible—as it has been in the past—will probably exacerbate population growth rates and the demand for another even-greener revolution. In fact, the human population could reach around 14 billion people by 2100 at current growth rates (FAO, 2006) and the number might be even higher if the proposed GGR succeeds.A true long-term view needs to embrace a far more extended timeframe and consider our great-grandchildren and the world they might live inAs the Earth''s carrying capacity is finite (Hueting, 2010; Pelletier, 2010), a GGR would lead to vanishing wilderness, resource exhaustion and, eventually, societal collapse. According to the latest estimates, we are already beyond the Earth''s carrying capacity and we would need around 1.2 Earths to support just the current population growth rate (WWF, 2008). In addition to resource exhaustion, another substantial problem of continued growth is the management of the waste generated by humankind, which at present is estimated to be around 30–40% of the food produced (Godfray et al, 2010). This mountain of refuse is likely to increase by orders of magnitude in the coming decades (Pelletier, 2010). Therefore, a GGR might be useful, at best, to cope with the near-term requirements of hungry humanity—the next two generations or so—but it is unsustainable in the medium to long term. Still, some solution is needed, as current and prognosticated starvation is ethically unacceptable and might lead to social conflict and war.In this context, the issue of equity or intra-generational social justice—despite the fact that it is mentioned as a premise in almost all proposals on food security—is rarely addressed. Almost everyone agrees that wealth and health should be equitably distributed throughout the world, but there are no firm proposals on how to achieve this goal and little progress has been made. It is a political problem that requires a political solution, but international organizations—notably the United Nations (UN) and its subordinate bodies—have not been able to tackle it, and there is little hope that they will in the current political climate.As the Earth''s carrying capacity is finite […], a GGR would lead to vanishing wilderness, resource exhaustion and, eventually, societal collapseThe inequality prevalent in the world serves the economic interest of the richest nations through the near-ubiquitous capitalist model, which equates development with increasing wealth, measured as the gross domestic product (GDP) of a country. Increasing globalization—with the recent demise of the socialist model—has promoted the export of the capitalist model to almost every country. As a result, and through the influence of organizations such as the World Trade Organization, the International Monetary Fund and the World Bank, capitalism has become the dominant economic model. Other issues such as international law, international security, economic development, social progress and human rights are subject to the political and economic interests of the richest economies. Social and environmental policies remain subordinate to capitalist concerns at both the local and regional scale (Pelletier, 2010). The inequality thus created is the cause of starvation and malnutrition in developing countries. Before 2005, more than 850 million people were undernourished. This number then increased by 75 million in only 2 years, owing mainly to the rise of wheat and maize prices for market reasons (Beddington, 2010). Today, hunger is not only a problem of overpopulation, but to a great extent, also of intra-generational injustice. This means that fighting starvation is a matter not only of growing more food, but also of creating social equity, which requires economic and political action.Future population growth and the corresponding demand for more food therefore support the current capitalistic model, which is based on economic growth and unequal wealth distribution. A GGR would be subject to this growth model; in other words, capitalism, not humanity, needs a GGR. Scientists should be aware of this and consider whether a GGR is really the best option from both a professional and personal point of view, as science should serve humanity and Earth, not any particular social, religious, ideological, political or economic system (Rull, 2010).Those who prefer a more sustainable path for future development might consider demand reduction—an option to avoid future food scarcity that is rarely considered (Westing, 2010). For their part, economists and politicians should also develop and implement alternative economic models that aim for a sustainable future for both humans and nature. The alternative—trying to reconcile economic growth, social justice and environmental safety—is akin to putting a square peg into a round hole (Lawn, 2010). In his 2008 book, The Bridge at the Edge of the World, the environmental advocate James Speth laments that modern capitalism is already out of control and that “growth is the enemy of environment. Economy and environment remain in collision” (Speth, 2009).Humanity has […] organized itself in such a way that different nations, ideologies, races, social classes and so on, compete with each as though they were ‘cultural species''There are alternative economic models that recognize ecological limits to human development and emphasize social equity. The first of these proposes a steady-state economy: one that has stopped growing in terms of GDP, but continues to improve quality of life and is maintained by an ecologically sustainable rate of resource throughput and a constant human population (Kerschner, 2010; Lawn, 2010). The second is a sustainable de-growth model that has been defined as “an equitable down-scaling of production and consumption that increases human well-being and enhances ecological conditions at the local and global level, in the short and long term” (Schneider et al, 2010). The paradigm is that human progress without economic growth is possible; it has been shown repeatedly that GDP per capita does not correlate with overall happiness above a certain level of satisfying people''s basic needs (Layard, 2010). According to these proposals, rich nations would need to start the transition to a steady-state economy through the reduction of GDP or de-growth within the next 5 years, and poor nations could take 20–40 years to make the transition in order to ensure a sustainable future. As many poor nations have the highest population growth rates, a first step should be to implement suitable controls to stabilize their populations with support from rich countries.…capitalism is a successful strategy with strong selective value to increase evolutionary fitnessThe defenders of de-growth emphasize that this process is not the same as recession or depression—there should be no social or quality of life deterioration—nor does it promote a return to a fictitious pre-industrial pastoral past. GDP reduction involves mainly components that require large-scale, resource-intensive production and socio-political and lifestyle changes (Schneider et al, 2010). Steady-state and de-growth models are based on the principle of ecological economics, which emphasizes the importance of the interactions between the environment and the economy, and of biophysical laws and constrains to human development (Costanza et al, 1997; Victor, 2010). Ecological economics is based on simple premises: the laws of thermodynamics, which state that the amount of energy in a closed system is constant and that any transformation degrades usable energy into entropy. All economic activities therefore deplete the available stock of usable energy and produce entropic waste; a closed system such as the Earth has a limited capacity to supply energy and material resources and to absorb the associated entropic waste (Pelletier, 2010).Among the different meanings of sustainability, ecological economics defends a so-called strong sustainability (Munda, 1997). This is in contrast to weak sustainability, which assumes an abundance of natural resources and that technological progress can increase the productivity of natural capital faster than it is being depleted. Weak sustainability could be considered a moderate version of the planetary ownership view (Bruce, 2008). By contrast, strong sustainability argues that natural capital—which provides raw materials for production and consumption, assimilates the resulting waste products, and provides amenity services and basic life-support functions on which human life depends—is largely non-substitutable (Neumayer, 2003; Dietz & Neumayer, 2007). The idea behind strong sustainability is to strike a balance between nature intervention and conservation—that is, the stewardship approach described by Bruce (2008). Despite its concern for nature, the idea of strong sustainability is still anthropocentric, as the primary objective is human survival and welfare. Therefore, strong sustainability could be viewed simply as a wiser form of planetary ownership than weak sustainability.Although steady-state and de-growth are interesting and promising proposals to meet the problem of food security, there are some concerns; namely, the considerable changes required of socio-political organizations and lifestyles, the adherence to an intrinsically anthropocentric concept of sustainability, and the lack of a consolidated programme to realize these ideas.Indeed, affluent democratic societies might be highly resistant to the necessary changes in lifestyle and consumption. A reduction of material living standards and consumption in industrialized countries would probably cause feelings of loss (Matthey, 2010). Few politicians or political parties with aspirations to government would be willing to defend such an unpopular proposal. Another obstacle in Western democratic systems is the short duration of each government, which is usually 4–5 years. Most governments are therefore reluctant to address problems that require large-scale, long-term changes. The problem is even more serious given that international organizations such as the UN, which were created specifically to meet such global challenges, remain subject to political and economic interests of the richer countries and therefore powerless to implement changes in such nations. Some have therefore proposed the creation of a new World Environmental Organization with the teeth and authority to legislate and enforce compliance (Pelletier, 2010).Economic crises such as the present one are excellent opportunities for questioning the dominant capitalist model…The problem of acceptance might be even worse in developing nations. The promise of capitalism has created expectations of wealth and consumption in these countries that people would be asked to renounce even before they had had a chance to enjoy them. Thus, population control is not sufficient, as most humans also need more food, better health and better living conditions. To mitigate this problem it has been proposed that developed countries should switch to a steady-state economy now, thereby leaving space for growth in the developing nations as a sign of intra-generational social justice (Kerschner, 2010). Of course, such economic growth should include effective population control in order to increment per capita income and to increase social and individual well-being. To make such growth sustainable, it would still require a GGR to increase food production and reduce the degradation of nature.Worldwide social justice is a complex issue that is beyond the scope of this article, but some ideas are pertinent in this context. Perhaps our lack of a species consciousness is a main obstacle to attaining goals such as intra-generational justice, the eradication of hunger, sustainable development and nature conservation—all of which are apparently desired by most people. Humanity has won its battles against its competitors—other violent, omnivorous species—but has organized itself in such a way that different nations, ideologies, races, social classes and so on, compete with each as though they were ‘cultural species''. In this context, capitalism is a successful strategy with strong selective value to increase evolutionary fitness. Some anthropologists believe that we are not yet humans, as we are still too attached to ancestral primate values such as selfishness, territoriality and violence (Carbonell & Sala, 2001). According to the same authors, the necessary species consciousness will emerge from altruism and the socialization of knowledge (Carbonell, 2007). Apart from the manifest ownership attitude of these anthropologists—whose ultimate aim is to replace the natural order with human organization of Earth—their concept of a global human species consciousness and how to attain it could be interesting for its use as a tool to address sustainable development under ecological economics principles.The formulation of ideas to achieve steady-state and de-growth economies is still in progress, but some clues to a solution can already be seen. For example, Lawn (2010) offers some macroeconomic considerations on how governments can regulate the private sector to facilitate the transition to a steady-state economy. Another interesting proposal is to reduce the dependence on markets and to develop alternative political and economic infrastructures with different values (Latouche, 2010). Steady-state and de-growth proposals are encouraging manifestations of the interest of certain economic sectors to develop credible and viable alternatives to uncontrolled growth, but more options are needed with special emphasis on reducing or avoiding anthropocentrism, and limiting or eliminating the prevalence of the market economy (Rull, 2010). Economic crises such as the present one are excellent opportunities for questioning the dominant capitalist model (Schneider et al, 2010; Johns, 2010). Now is the time for economic creativity and political will.…molecular research focused on food improvement is justified, but its contribution to either development model depends […] on social and political interestsIn the context of GGR, scientific research and technological development are parts of the so-called sustainable intensification to produce more food. In the steady-state or de-growth models, science and technology are tools to reduce the land needed to produce a given amount of food. The key is the big picture; molecular research focused on food improvement is justified, but its contribution to either development model depends—as do most, if not all, scientific contributions—on social and political interests. In this regard, the scientific and technological developments proposed in the context of a GGR, such as crop improvement and protection, sustainable livestock farming, fishing and aquaculture improvement, mechanization, engineering, nanotechnology and diet changes, should be encouraged anyway, as these can contribute greatly to more efficient and hopefully safer food production practices in the future.In summary, while global capitalism needs a GGR to continue along its unsustainable path, there are alternative models of human development that accept and address the biophysical constraints on economic and population growth on Earth. Some steady-state and de-growth alternatives have been proposed, based on the emerging discipline of ecological economics, but these would require a political and societal revolution, and a reassessment of the role of the market economy and true nature conservation. However, the basic principles of ecological economics seem potentially useful if we are to avoid a succession of GGRs that exhaust the Earth''s resources. The acceptance of those principles could represent a first step towards a better world.It is beyond all doubt that scientists defending a GGR have good intentions. But this should be done in a different scenario than the utopia of unlimited growth. Otherwise, politicians, stakeholders and the public in general might get a wrong idea of what is considered right from a scientific point of view and, what is worse, they might lose confidence in science and its practitioners.? Open in a separate windowValentí Rull     

Who’s a Quack?

Are there any characteristics by which we can reliably identify and distinguish quackery from genuine medicine? A commonly offered criterion for the distinction between medicine and quackery is science: genuine medicine is scientific; quackery is non-scientific. But it proves to be the case that at the boundary of science and non-science, there is an entanglement of considerations. Two cases are considered: that of homoeopathy and that of the Quantum Booster. In the first case, the degree to which reported phenomena that question established theory should be doubted arises; in the second case, the status of pleomorphism as a scientifically plausible doctrine is discussed. The application of the criterion of being scientific to these cases reveals something of the nature and density of the entanglement.     

Glycerokinase activity in brown adipose tissue: a sympathetic regulation?

The effect of brown adipose tissue (BAT) sympathetic hemidenervation on the activity of glycerokinase (GyK) was investigated in different physiological conditions. In rats fed a balanced diet, the activity of the enzyme was approximately 50% lower in BAT-denervated pads than in intact, innervated pads. In rats adapted to a high-protein, carbohydrate-free diet, norepinephrine turnover rates and BAT GyK activity were already reduced, and BAT denervation resulted in a further decrease in the activity of the enzyme. Cold acclimation of normally fed rats at 4 degrees C for 10 days markedly increased the activity of the enzyme. Cold exposure (4 degrees C) for 6 h was insufficient to stimulate BAT GyK, but the activity of the enzyme was already increased after 12 h of cold exposure. The cold-induced BAT GyK stimulation was completely blocked in BAT-denervated pads. The data indicate that an adequate sympathetic flow to BAT is required for the maintenance of normal levels of GyK activity and for the enzyme response to situations, such as cold exposure, which markedly increase BAT sympathetic flow.     

The KEOPS complex: a rosetta stone for telomere regulation?

The detailed mechanisms underlying telomere capping and its relationship to telomerase activity are still unclear, although many proteins have been implicated in either or both processes. In this issue of Cell, the surprising identification of a new complex, called KEOPS, which promotes both telomere uncapping and elongation is presented.     

Chemical regulation of nitric oxide: a role for intracellular myoglobin?

The detailed chemistry of nitric oxide (*NO) and regulation of this potent signal molecule through interactions with cellular components are complex and not clearly understood. In the vasculature, *NO plays a crucial role in vessel dilation by activating soluble guanylyl cyclase (sGC) in vascular smooth muscle cells (VSMC). *NO is responsible for maintaining coronary blood flow and normal cardiac function. However, *NO is a highly reactive molecule and this reactivity toward a range of alternate substrates may interfere with the activation of its preferred molecular target within VSMC. Interestingly, marked changes to *NO homeostasis are linked to disease progression. Thus, the physiological concentration of *NO is carefully regulated. Myoglobin is a haem-containing protein that is present in relatively high concentration in cardiac and skeletal muscle. Recently, the presence of myoglobin has been confirmed in human smooth muscle. The role of intracellular myoglobin is generally accepted as that of a passive di-oxygen storage protein. However, oxygenated myoglobin readily reacts with *NO to yield higher order N-oxides such as nitrate, while both the ferrous and ferric forms of the protein form a stable complex with *NO. Together, these two reactions effectively eliminate *NO on the physiological time-scale and strongly support the idea that myoglobin plays a role in maintaining *NO homeostasis in tissues that contain the protein. Interestingly, human myoglobin contains a sulfhydryl group and forms an S-nitroso-adduct similar to haemoglobin. In this article we discuss the potential for human myoglobin to actively participate in the regulation of *NO by three distinct mechanisms, namely oxidation, ligand binding, and through formation of biologically active S-nitroso-myoglobin.     

Ageing and the regulation of protein synthesis: a balancing act?

Ageing in diverse species ranging from yeast to humans is associated with extensive changes in both general and specific protein synthesis. Accumulating evidence now indicates that these alterations are not simply a corollary of the ageing process but, rather, they have a causative role in senescent decline. Indeed, interfering with mRNA translation significantly influences longevity. Interestingly, the mechanisms that control mRNA translation interface with intricate, conserved signalling pathways and specific conditions that regulate ageing, such as the insulin-insulin growth factor 1 signalling pathway and caloric restriction. This emerging relationship reveals that protein synthesis is a novel determinant of ageing in diverse organisms such as yeast, worms, flies and mice and can thus be considered as a universal component of the ageing process.     

Diagnostic kits in parasitology: which controls?

The development of new diagnostic tools particularly for some parasitic "neglected diseases", is slowed or even hindered by limited resources assigned for basic and applied research in public institution and private sector. Even if the time-line and costs needed for developing a new In Vitro Diagnostic (IVD) test are generally lower compared to vaccines or new drugs, industry is poorly engaged in investing resources due to the perception of limited markets. To accelerate the development of diagnostics for the world's most deadly diseases, the World Health Organization's (WHO) Special Programme for Research and Training in Tropical Diseases (TDR), the United Nations Development Programme, the World Bank and the Gates Foundation, last year launched a new initiative, FIND (Foundation for Innovative New Diagnostics, www.finddiagnostics.org). The aim is to "apply the latest biotechnology innovations to develop and validate affordable diagnostic tests for diseases of the developing world". Ideally, a new diagnostic test should be accurately evaluated prior to use in medical practice. The first step would be a pre-clinical evaluation, an analytic study to determine its laboratory performance. A crucial point in this phase is the calibration of reagents (antigens, antibodies, DNA probes, etc.) against a standard reference preparation. WHO, through the WHO International Laboratories for Biological Standards, "provides International Biological Reference Preparations which serve as reference sources of defined biological activity expressed in an internationally agreed unit" (www.who.int/biologicals/IBRP/index.htm). Standardization allows "comparison of biological measurements worldwide" and ensures the reliability of diagnostic procedures. These preparations are generally intended for use in the characterization of the activity of secondary reference preparations (regional, national or in-house working standards). Unfortunately, international reference standards for parasitic diseases are not available at present, except for Toxoplasma antibodies. The first international standard reagent for Anti-Toxoplasma Serum was established in 1968 and at present, an international standard reference serum, Anti-toxoplasma serum, human TOXM is available at the National Institute for Biological Standards and Control (NIBSC) in UK. Several collaborative, multicenter studies were carried out to assess the performance of different methods and commercial tests for the diagnosis of toxoplasmosis, by providing to participating laboratories a panel of well-defined sera to be tested. A four-phase process following well-accepted methodological standards for the development of diagnostics, analogous to those internationally accepted for drugs and vaccines was recently proposed. The pre-clinical evaluation, the analytic study to assess sensitivity, specificity, predictive values in laboratory (phase I), should be followed by a proof of principle study to distinguish diseased from healthy persons in easily accessible populations (phase II). The evaluation of test performance in populations of intended use (phase III), and finally the delineation of cost-effectiveness and societal impact of new tests in comparison with existing tools (phase IV) should complete the validation procedure. In this context, national regulatory agencies play a major role in pre-market approval and post-market surveillance of IVDs. The European Community in 1998 approved a directive (Directive 98/79/EC) which rules the marketing of IVD medical devices, in order to harmonise the performance levels and standards in European countries. But, among IVDs for parasitic diseases, only those to detect congenital toxoplasmosis are submitted to defined procedures to provide the verification of products before their placing on the market and the surveillance after their marketing by a notified body, which perform appropriate examinations, tests and inspections to production facilities to verify if the device meets the requirements of the directive. In U.S.A., the Food and Drug Administration (FDA), through the Office of In Vitro Diagnostic Device Evaluation and Safety (OIVD), provides a comprehensive and regulatory activity for IVDs through pre-market evaluation and post-market surveillance. In developing countries, the scarcity of resources limits the procedures through which the national control authority can assure safety, quality and efficacy of products marketed, both imported and locally manufactured.     

Biological Clocks: Who in This Place Set Up a Sundial?

How do circadian rhythms, alarm clocks and the light/dark cycle interact? The concept of social jetlag is informing our appreciation of the tensions and consequences of imposing an artificial temporal order upon our biology.