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The diversity of extrasolar planets discovered in the last decade shows that we should not be constrained to look for life in environments similar to early or present-day Earth. Super-Earth exoplanets are being discovered with increasing frequency, and some will be able to retain a stable, hydrogen-dominated atmosphere. We explore the possibilities for photosynthesis on a rocky planet with a thin H[subscript 2]-dominated atmosphere. If a rocky, H[subscript 2]-dominated planet harbors life, then that life is likely to convert atmospheric carbon into methane. Outgassing may also build an atmosphere in which methane is the principal carbon species. We describe the possible chemical routes for photosynthesis starting from methane and show that less energy and lower energy photons could drive CH[subscript 4]-based photosynthesis as compared with CO[subscript 2]-based photosynthesis. We find that a by-product biosignature gas is likely to be H[subscript 2], which is not distinct from the hydrogen already present in the environment. Ammonia is a potential biosignature gas of hydrogenic photosynthesis that is unlikely to be generated abiologically. We suggest that the evolution of methane-based photosynthesis is at least as likely as the evolution of anoxygenic photosynthesis on Earth and may support the evolution of complex life.

I report on five years’ testing of what makes a happy team, using students in a Bioscience Entrepreneurship Masters programme at Cambridge University as a test-bed. I looked at measures of personality (using the IPIP test for the Big Five personality characteristics) and a measure of work style derived from the time of submission of work that I term Deadline Brinkmanship. I find that teams selected to have a similar working style are generally happier working together than those selected by other criteria. Entrepreneurial activity is uncorrelated with psychological characteristics in this study, but is slightly correlated with working style and the willingness to accept a “good enough” result now rather than an ideal result in the future. I conclude that it is important for a nascent entrepreneurial team to work together on an important, deadline-driven task before committing to a new venture.Â

Earth life is built from a quite restricted set of chemicals. Is this an accident of evolution, or are there reasons for the patterns of similarity and diversity in metabolism? I summarize several studies looking at how life has explored “chemical space”, and seeking explanations for the nature of biochemistry. The properties of synthetic alternatives to DNA have lead to a hypothesis about what the features that any genetic material must have, providing a rationale for the incorporation of phosphate into DNA. Synthesis and computational studies of possible amino acids have been synergistic in understanding the limits to which the 20 main proteinaceous amino acids are chemically inevitable and the extent to which they are a frozen accident from the origin of life. A broader exploration of chemical space including all of metabolism shows that metabolism is actually crowded into a limited region of the space of possible chemicals. Using a wide dataset of measurement of the toxicity of chemicals, I have shown that this crowding has important implications for how new chemistry can be added to life, which could in principle be developed into a set of constraints on how any metabolism could evolve. Biochemistry is often constrained to specific chemical function, but not always limited to one molecule to carry out that function. These initial results provide hope that there are computationally tractable approaches to understanding why biochemistry is as it is.

Investment in start-up biotech. companies outside the USA has essentially disappeared. VC investment in biotechnology and healthcare as a whole has nearly returned to pre-2008 levels, but almost all is in later stage opportunities. But companies continue to be founded, and continue to flourish. We examine the VC investment patterns for the past 7 years, and show that a start-up today can expect little VC support. We show from companies’ financial records that companies are adopting financial models based on angel investment, grants and revenue, and moving away from business models that need substantial investment. There is a time lag, but government and research council policy is beginning to recognize and align with the new investment realities. We believe this trend will accelerate as internet-mediated angel investing, such as crowd-funding schemes seen in other sectors, become a developing force in the next decade.

This paper analyses the business model on which genomics companies base their future value as a result of performing discovery programmes in collaboration with partner companies who then develop products from the knowledge generated. A model of the deal-flow and consequent cash requirements and generation of a company delivering discovery genomics or pharmacogenomics resources and technology in presented. It is demonstrates that on a net present value (NPV) basis, investing in target discovery using genomics is not as attractive as public valuations of the companies would suggest, and rarely provides Internal Rates of Return (IRR, the discount rate at which NPV is zero) greater than the NASDAQ composite average. A realistic model of a company performing only genomics target discovery has an IRR of around 12%; this is below the majority of established manufacturing company stocks. The business model is independent of technology details: exactly the same economics apply to proteomics, transcriptomics and other investment-intensive discovery technologies. It is concluded that venture capital (VC) investment in genomics will be driven by the likelihood of a rapid exit rather than the genuine underlying value of the company, and that private investors looking to build long-term value will increasingly look to other technologies as the problems of discovery technology companies become more apparent.

The need to publish ideas so that they can be explored, debated and extended by others before they are fully tested in the lab or the clinic is in conflict with the need to patent those ideas to provide a commercial incentive to apply them. I discuss why this conflict occurs, why it is important, and suggest three ways to get round it: root-and-branch reform of patent law (which seems impossible), extension of the US system's ‘grace period’ between publishing and filing a patent to longer times in the US and implementing the same system in other countries (which seems unlikely to happen), and binding readers of journals with a network of optional confidentiality agreements that allow publication but not citation without the authors’ permission. This latter appears too complex and conflicting an idea to work either, but while many conflicts with common scientific practice exist, the complexity of the system need not deter us, as at root the idea is simple and so it could be managed by software instead of patent lawyers.

(Abridged) Super Earth exoplanets are being discovered with increasing frequency and some will be able to retain stable H2-dominated atmospheres. We study biosignature gases on exoplanets with thin H2 atmospheres and habitable surface temperatures, by using a model atmosphere with photochemistry, and biomass estimate framework for evaluating the plausibilty of a range of biosignature gas candidates. We find that photochemically produced H atoms are the most abundant reactive species in H2 atmospheres. In atmospheres with high CO2 levels, atomic O is the major destructive species for some molecules. In sun-Earth-like UV radiation environments, H (and in some cases O) will rapidly destroy nearly all biosignature gases of interest. The lower UV fluxes from UV quiet M stars would produce a lower concentration of H (or O) for the same scenario, enabling some biosignature gases to accumulate. The favorability of low-UV radiation environments to in an H2 atmosphere is closely analogous to the case of oxidized atmospheres, where photochemically produced OH is the major destructive species. Most potential biosignature gases, such as DMS and CH3Cl are therefore more favorable in low UV, as compared to solar-like UV, environments. A few promising biosignature gas candidates, including NH3 and N2O, are favorable even in solar-like UV environments, as these gases are destroyed directly by photolysis and not by H (or O). A more subtle finding is that most gases produced by life that are fully hydrogenated forms of an element, such as CH4, H2S, are not effective signs of life in an H2-rich atmosphere, because the dominant atmospheric chemistry will generate such gases abiologically, through photochemistry or geochemistry. Suitable biosignature gases in H2-rich atmospheres for super Earth exoplanets transiting M stars could potentially be detected in transmission spectra with the JWST., ApJ, in press

Sulfur gases are common components in the volcanic and biological emission on Earth, and are expected to be important input gases for atmospheres on terrestrial exoplanets. We study the atmospheric composition and the spectra of terrestrial exoplanets with sulfur compounds (i.e., H2S and SO2) emitted from their surfaces. We use a comprehensive one-dimensional photochemistry model and radiative transfer model to investigate the sulfur chemistry in atmospheres ranging from reducing to oxidizing. The most important finding is that both H2S and SO2 are chemically short-lived in virtually all types of atmospheres on terrestrial exoplanets, based on models of H2, N2, and CO2 atmospheres. This implies that direct detection of surface sulfur emission is unlikely, as their surface emission rates need to be extremely high (>1000 times Earth's volcanic sulfur emission) for these gases to build up to a detectable level. We also find that sulfur compounds emitted from the surface lead to photochemical formation of elemental sulfur and sulfuric acid in the atmosphere, which would condense to form aerosols if saturated. For terrestrial exoplanets in the habitable zone of Sun-like stars or M stars, Earth-like sulfur emission rates result in optically thick haze composed of elemental sulfur in reducing H2-dominated atmospheres for a wide range of particle diameters (0.1-1 micron), which is assumed as a free parameter in our simulations. In oxidized atmospheres composed of N2 and CO2, optically thick haze, composed of elemental sulfur aerosols (S8) or sulfuric acid aerosols (H2SO4), will form if the surface sulfur emission is 2 orders of magnitude more than the volcanic sulfur emission of Earth. Although direct detection of H2S and SO2 by their spectral features is unlikely, their emission might be inferred by observing aerosol-related features in reflected light with future generation space telescopes., Accepted for publication on the ApJ

Peer review is a widely accepted instrument for raising the quality of science. Peer review limits the enormous unstructured influx of information and the sheer amount of dubious data, which in its absence would plunge science into chaos. In particular, peer review offers the benefit of eliminating papers that suffer from poor craftsmanship or methodological shortcomings, especially in the experimental sciences. However, we believe that peer review is not always appropriate for the evaluation of controversial hypothetical science. We argue that the process of peer review can be prone to bias towards ideas that affirm the prior convictions of reviewers and against innovation and radical new ideas. Innovative hypotheses are thus highly vulnerable to being "filtered out" or made to accord with conventional wisdom by the peer review process. Consequently, having introduced peer review, the Elsevier journal Medical Hypotheses may be unable to continue its tradition as a radical journal allowing discussion of improbable or unconventional ideas. Hence we conclude by asking the publisher to consider re-introducing the system of editorial review to Medical Hypotheses.

Author Manuscript September 24, 2013, Biosignature gas detection is one of the ultimate future goals for exoplanet atmosphere studies. We have created a framework for linking biosignature gas detectability to biomass estimates, including atmospheric photochemistry and biological thermodynamics. The new framework is intended to liberate predictive atmosphere models from requiring fixed, Earth-like biosignature gas source fluxes. New biosignature gases can be considered with a check that the biomass estimate is physically plausible. We have validated the models on terrestrial production of NO, H[subscript 2]S, CH[subscript 4], CH[subscript 3]Cl, and DMS. We have applied the models to propose NH[subscript 3] as a biosignature gas on a "cold Haber World," a planet with a N[subscript 2]-H[subscript 2] atmosphere, and to demonstrate why gases such as CH[subscript 3]Cl must have too large of a biomass to be a plausible biosignature gas on planets with Earth or early-Earth-like atmospheres orbiting a Sun-like star. To construct the biomass models, we developed a functional classification of biosignature gases, and found that gases (such as CH[subscript 4], H[subscript 2]S, and N[subscript 2]O) produced from life that extracts energy from chemical potential energy gradients will always have false positives because geochemistry has the same gases to work with as life does, and gases (such as DMS and CH[subscript 3]Cl) produced for secondary metabolic reasons are far less likely to have false positives but because of their highly specialized origin are more likely to be produced in small quantities. The biomass model estimates are valid to one or two orders of magnitude; the goal is an independent approach to testing whether a biosignature gas is plausible rather than a precise quantification of atmospheric biosignature gases and their corresponding biomasses., Foundational Questions Institute (FQXi)

Grainger et al . (Reports, 13 April 2012, p. 245) suggest that baboons can discriminate words from nonwords on the basis of two-letter (bigram) frequencies. This ability can also be attributed to baboons being able to recognize specific letters (i.e., shapes) in specific positions in their four-letter words, without reference to letter or bigram frequencies.

Redox chemistry is central to life on Earth. It is well known that life uses redox chemistry to capture energy from environmental chemical energy gradients. Here, we propose that a second use of redox chemistry, related to building biomass from environmental carbon, is equally important to life. We apply a method based on chemical structure to evaluate the redox range of different groups of terrestrial biochemicals, and find that they are consistently of intermediate redox range. We hypothesize the common intermediate range is related to the chemical space required for the selection of a consistent set of metabolites. We apply a computational method to show that the redox range of the chemical space shows the same restricted redox range as the biochemicals that are selected from that space. By contrast, the carbon from which life is composed is available in the environment only as fully oxidized or reduced species. We therefore argue that redox chemistry is essential to life for assembling biochemicals for biomass building. This biomass-building reason for life to require redox chemistry is in addition (and in contrast) to life's use of redox chemistry to capture energy. Life's use of redox chemistry for biomass capture will generate chemical by-products-that is, biosignature gases-that are not in redox equilibrium with life's environment. These potential biosignature gases may differ from energy-capture redox biosignatures.

Microbial life on Earth uses a wide range of chemical and energetic resources from diverse habitats. An outcome of this microbial diversity is an extensive and varied list of metabolic byproducts. We review key points of Earth-based microbial metabolism that are useful to the astrophysical search for biosignature gases on exoplanets, including a list of primary and secondary metabolism gas byproducts. Beyond the canonical, unique-to-life biosignature gases on Earth (O2, O3, and N2O), the list of metabolic byproducts includes gases that might be associated with biosignature gases in appropriate exoplanetary environments. This review aims to serve as a starting point for future astrophysical biosignature gas research. Key Words: Exoplanet—Biosignature—Microbial redox reactions. Astrobiology 12, 61–82.

We present a comprehensive photochemistry model for exploration of the chemical composition of terrestrial exoplanet atmospheres. The photochemistry model is designed from the ground up to have the capacity to treat all types of terrestrial planet atmospheres, ranging from oxidizing through reducing, which makes the code suitable for applications for the wide range of anticipated terrestrial exoplanet compositions. The one-dimensional chemical transport model treats up to 800 chemical reactions, photochemical processes, dry and wet deposition, surface emission and thermal escape of O, H, C, N and S bearing species, as well as formation and deposition of elemental sulfur and sulfuric acid aerosols. We validate the model by computing the atmospheric composition of current Earth and Mars and find agreement with observations of major trace gases in Earth's and Mars' atmospheres. We simulate several plausible atmospheric scenarios of terrestrial exoplanets, and choose three benchmark cases for atmospheres from reducing to oxidizing. The most interesting finding is that atomic hydrogen is always a more abundant reactive radical than the hydroxyl radical in anoxic atmospheres. Whether atomic hydrogen is the most important removal path for a molecule of interest also depends on the relevant reaction rates. We also find that volcanic carbon compounds (i.e., CH4 and CO2) are chemically long-lived and tend to be well mixed in both reducing and oxidizing atmospheres, and their dry deposition velocities to the surface control the atmospheric oxidation states. Furthermore, we revisit whether photochemically produced oxygen can cause false positives for detecting oxygenic photosynthesis, and find that in 1-bar CO2-rich atmospheres oxygen and ozone may build up to levels that have been previously considered unique signatures of life, if there is no surface emission of reducing gases..., Comment: Accepted for publication on ApJ

This article reports the preliminary results of a search for patterns in the strand asymmetry and local self-similarity in mammalian nuclear DNA. The study provides the basis for statistical investigations of larger-scale DNA structure, which may be correlated with genetic mechanisms or with gene function.

DNA manipulation techniques have allowed the isolation and identification of many genes which cause disease in man. The same techniques are now being automated, and are on the threshold of application to more common and more complex genetic predispositions to diseases such as diabetes and schizophrenia. This article outlines the technology behind this development, and discusses some of the social, legal and ethical difficulties that widespread screening for genetic traits will raise. It is argued that these issues must be considered now, so that considered social responses to this technology are in place in the five years it is likely to take to develop

VC exists because it promises to invest in bright new companies and give them the cash to grow, thus generating share price rise and the chance of substantial profit on their investment. The sections above show (in rather tedious detail) that it does not do so, and that the ‘gap’ in finance in Europe is in fact a reflection of this. I have argued that this is not because companies are not there to invest in, nor that the science, management, entrepreneurial drive or other features are not ready to feed the VC machine with raw stock. I have also touched on how underinvestment increases biotech companies’ chances of failure. This is not because European VCs have less funds than US ones: fund sizes across all stages of the fund life cycle are similar [17]. So why should VCs pursue this policy?

This book is slightly unusual. Most business books are about how to run a successful business. This one aims to be a detailed, fact-based primer on how to fail in one of the world’s most exciting and fast-moving industrial sector — biotechnology.

The last chapter described how VCs abrogate management authority, fail to provide the support they promise to management and instigate management change when it is counterproductive to the VC’s own goals of stock value appreciation and IPO. An explanation for this rather odd set of observations is that the VC has a deep knowledge of how a biotech business should be run and, while they do not have the time to provide that understanding to the company management, they nevertheless can direct the management to that end, and simply get rid of them if they disagree rather than try to work with them to change their mode of operation. This could be effective if the investors themselves had a clear idea about, or a good track record in, managing the affairs of investee companies. This chapter tests this by examining the effects of investors on the company’s business model, the next by examining their effects on the execution of that model.

Why do new companies fail? We have looked briefly at aspects of management and entrepreneurship, the usual scapegoats for company failure. However, the objective evidence is that overwhelmingly companies fail through undercapitalisation.

I have reached the point where I am going to try to suggest some solutions to the problems outlined above. As I warned at the start, none of these are complete or enormously compelling. Complex problems rarely have simple, dramatic solutions: they yield to incremental improvement on a number of fronts. This is the approach I advocate.

The wheels of government grind exceeding slow: while European states and regions modify the underlying legal and economic structure that encourages the VCs’ business model, we can ask what other business people might do to avoid its fallout.

The previous chapters have outlined how VCs invest too little (for reasons that do not stack up), and then drive companies to a series of adverse decisions and business outcomes while failing to support the management they have emasculated with contractual arrangements. They appoint the wrong people, chose the wrong business strategies and block the companies’ attempts to do anything about it. It is of course a one-sided story: there are many factors contributing to Europe’s lacklustre biotechnology story, and many factors contributing to the few stars in the continent’s dim sky. But the sections above show that VCs both control the companies and act so as to reduce their chances of success, through underinvestment and poor management. Their influence is so all pervading and their role in the industry so crucial that they must be a significant factor in its failure, and we have identified some of the mechanisms through which this occurs.

This is not a book about the technology of biotechnology, but about the business of biotechnology. The latter is dependent on the former, but can be described without ever explaining what a gene is.1 I will try to keep it that way.

As we have seen, VCs claim that they support their companies in a variety of ways, and even if the reality of time management means that this is an implausible claim, surely they would not go out of their way to sabotage an investee company? Of course they do not. But the effect of the way they invest is to achieve a similar goal. To explain this I will have to digress into a short discussion on share structures in VC-invested startup companies.

The European biotechnology industry is, therefore, smaller, less productive and growing far more slowly than its US counterpart, and this malaise is not related to Europe not being part of the US, nor is the UK’s relatively poor showing because it is smaller than the US. The companies are also ‘younger’. VC-backed biotech companies typically start out to do research, discovering a product and only when that product is mature enough for a market do they fill out the organisational structure to include marketing, sales, manufacturing and the other functions expected of a fully fledged business. By the end of 2006, US public biotech companies had four times the employees of European ones, but only 1.3 times as many employed in R&D, that is, the European industry was far more focused on the early stages of the biotech business model [33].

Thus the flower of biotechnology is a small weed in Europe compared to the giant redwood of the US. Why should this happen? Before delving into what I think is the main reason — the business practices of the VC groups that control the industry — it is worthwhile discussing the ‘reasons’ that are usually given, and showing why they are at most a minor cause of the relative lack of growth and frequent commercial and financial failure of the European industry. In this section I will explicitly leave out financial reasons such as the structure of the capital markets — we will deal with this in Chapter 6.

Not all businesses require VC investment — indeed, few do, which is a good thing as otherwise hardly any new businesses would be created. ‘Normal’ business is dependent not on start-up capital but on revenue, and specifically on cash reserves built up from profit to buffer revenue fluctuations and provide capital for growth.

Chronic Fatigue Syndrome is a physiological state in which the patient feels high levels of fatigue without an obvious organic cause, which affects around 1 in 400 people in the developed world. A wide range of causes have been suggested, including immune or hormonal dysfunction, viral or bacterial infection, and psychological somatization. It is likely that several causes are needed to trigger the disease, and that the triggers are different from the mechanisms that maintain fatigue over months or years. Many treatments have been tested for CFS, with very limited success - a programme of combined CBT and graded exercise shows the most effect. I suggest that patients with CFS have a reduced ability to increase mitochondrial energy production when exertion requires it, with fewer mitochondria that are each more efficient, and hence nearer to their maximum energy output, than normal. A range of indirect evidence suggests that the renin-angiotensin system stimulates mitochondrial responsiveness and reduces mitochondrial efficiency: chronic under-stimulation of this system could contribute to CFS aetiology. If correct, this means that CFS can be successfully treated with RAS agonists (eg angiotensin mimetics), or adrenergic agonists. It also suggests that there will be a positive link between the use of adrenergic- and RAS-blocking drugs and CFS incidence, and a negative link between adrenergic agonist use and CFS.

We have used Fragmentation Sequencing logic to analyse the repetition structure of several large human genomic genes. The method, based on a proposed laboratory scheme for DNA sequencing, detects short sequences which are repeated near, but not necessarily adjacent, to each other (cryptically simple DNA). We find a low frequency of such repeats. There is a slight excess of such repeats in introns over exons, and a slight but significant excess in genomic DNA over random DNA, confirming that cryptically simple sequences are over-represented in the genome. The analysis suggests that Fragmentation Sequencing will be a suitable method for sequencing large mammalian genes.

Summary Self-experimentation is an efficient, productive and proven way to generate new treatments for mild and serious disease. But it is limited by materials available to the individual and the amount of testing one person can do. I advocate the formation of Biomedical Mutual Organizations, self-funded groups of individuals that provide mutual support for exploring new ideas in medical treatment. Such groups could achieve three things. Firstly, they could pool analytical services to validate the quality of materials and analytical services used in self-testing and self-medication, including verification of the identity and purity of medicine ingredients sourced from non-traditional sources. Secondly, they could pool resources to conduct group experiments in new treatments, interpret the results, and generate new hypotheses which could in turn be tested. Thirdly they could conduct more formal clinical trials on the group as a whole of new, indeed radical, therapies, in effect becoming a self-funded biotechnology company. While many practical objections remain to all of these, especially the last, and the last option may actually be illegal in some countries, some of the ethical objections that prevent such arrangements outside the context of a Mutual Organizations are overcome by the alignment of interests of those involved.

Prediction of how drugs are absorbed, metabolized, distributed round the body, and excreted is increasingly important to the design of new medicines. However, it is too complex to model rigorously. Prediction algorithms are primarily based on databases of known examples, which are mined for simple rules, more complex mathematical algorithms, or rules sets. Many modeling techniques have been applied, and many ways of describing a molecule to the computer have been tested. I discuss the application of these methods for predicting whether a drug will be absorbed through the intestines, including whether it will be soluble, transported in or out by cell membrane transporters, and whether it will be metabolized, and for predicting penetration into the brain. Advanced statistical and machine learning techniques can generate good algorithms for approximating these quantities. However, predictions are not yet good enough to integrate into a “virtual human”. The main limitation is that the algorithms need more experimental data to encompass the complexity and variability of biological systems, as well as better, more biologically relevant ways of describing the molecules to the computer. Keywords: ADME; oral bioavailability; drug design; blood–brain barrier; P-gp; CYP; virtual biology; in silico; DMPK

This paper analyses how UK academics can make money from their expertise, other than through earning their salary. Using statistics from the success rate and likely remuneration from recent examples, four options are discussed: licensing their intellectual property through their institution's technology transfer office, owning shares in a 'spin-out' company, personal consulting and writing books. The case of the 'average' academic who does not actively pursue any of these goals, the 'active' academic who pursues any one of them, and the top tier academic who is in the top 10 per cent of their profession worldwide are examined. In all cases, consulting is the most economically rewarding option. For the 'average' academic, being involved in a venture-funded start-up is the worst.

Abnormalities of gene structure or expression are commonly found in cancers, where they are used as prognostic markers, predicting the likely severity of disease or chances of response to therapy. An odds ratio (OR) of

It has been widely suggested that life based around carbon, hydrogen, oxygen, and nitrogen is the only plausible biochemistry, and specifically that terrestrial biochemistry of nucleic acids, proteins, and sugars is likely to be "universal." This is not an inevitable conclusion from our knowledge of chemistry. I argue that it is the nature of the liquid in which life evolves that defines the most appropriate chemistry. Fluids other than water could be abundant on a cosmic scale and could therefore be an environment in which non-terrestrial biochemistry could evolve. The chemical nature of these liquids could lead to quite different biochemistries, a hypothesis discussed in the context of the proposed "ammonochemistry" of the internal oceans of the Galilean satellites and a more speculative "silicon biochemistry" in liquid nitrogen. These different chemistries satisfy the thermodynamic drive for life through different mechanisms, and so will have different chemical signatures than terrestrial biochemistry.

The use of organosilicon chemistry in drug design is reviewed. The field of bioorganosilicon chemistry, which sprung up in the 1970s to exploit the opportunities of silicon for drug design, is currently being developed into a practical and commercial enterprise. This review is mainly focused on two different approaches: (i) synthesizing a silicon analog of a known drug in which one carbon atom has been replaced by a silicon atom, with the rest of the molecule being identical (carbon/silicon switch, sila-substitution); (ii) synthesizing completely new silicon-based classes of compounds (the carbon analogs of which do not exist) that exploit specific features of silicon chemistry to address a well-validated target.

This review discusses evolutionary and adaptive methods for predicting oral bioavailability (OB) from chemical structure. Genetic Programming (GP), a specific form of evolutionary computing, is compared with some other advanced computational methods for OB prediction. The results show that classifying drugs into 'high' and 'low' OB classes on the basis of their structure alone is solvable, and initial models are already producing output that would be useful for pharmaceutical research. The results also suggest that quantitative prediction of OB will be tractable. Critical aspects of the solution will involve the use of techniques that can: (i) handle problems with a very large number of variables (high dimensionality); (ii) cope with 'noisy' data; and (iii) implement binary choices to sub-classify molecules with behavior that are qualitatively different. Detailed quantitative predictions will emerge from more refined models that are hybrids derived from mechanistic models of the biology of oral absorption and the power of advanced computing techniques to predict the behavior of the components of those models in silico.

Observations of large populations of ageing organisms have suggested that the exponential increase in the rate of age-related mortality (Gompertz rule) declines in extreme old age, and that the mortality of the extremely long-lived is independent of age. I show that this phenomenon is an expected outcome of ageing being the effect of stochastic failure of highly interconnected networks of elements with constant failure rates, and does not require the postulation of a separate ‘long-lived’ population of individuals.

Hypotheses need not be completely right to be useful. A hypothesis that explains an important aspect of the world, but not all of the world, can stimulate new ideas and new experiments which take science forward. Phlogiston is a typical case study. While not universally accepted at the time, and subsequently proved to be wrong, the hypothesis that there was a ‘fire-giving’ substance in inflammable materials prompted the development of quantitative chemistry, and the subsequent discovery of oxygen. Hypotheses today do not have to explain all aspects of the world perfectly. But they should be honest about those aspects they do not explain, and demonstrate some humility in their limitations. It is very unlikely that a single idea explains everything in a biological system. Theorists should recognise this: if they do not, their readers will, and will discount their ideas because of their lack of awareness of their context. Humility may get you a hearing.

Papers submitted to Bioscience Hypotheses should be innovative, clear, compatible with at least most of the facts, and testable. Not all good, new, challenging ideas manage these exacting standards. Editorial policy has been altered to include both an increased role for peer advice and an occasional role for editorial advice to authors to bring out the ideas in a form that I think most likely to attract interest from our readership.