Combinatorial innovation, evidence from patent data, and mandated innovation

This dissertation explores the implications of a new model of knowledge production. In my model, researchers have access to a set of primitive knowledge elements that can be combined to form ideas, where a new combination is a new idea. Underlying parameters governing the connections between elements stochastically determine whether a given combination yields a useful idea (some elements tend to work well together, and others do not). These underlying parameters are unknown to researchers, but as they attempt to combine elements and create ideas, they observe signals which they use to improve their beliefs via Bayesian updating. I embed this production function into a simple model of research incentives, where a firms receive a reward for discovering new and useful combinations, but pay a cost to conduct research. I investigate empirically these predictions using a large dataset on US utility patents: all 8.3 million utility patents granted between 1836 and 2012. From this analysis, I find that the probability a pair of knowledge “elements” (now proxied by technology classifications assigned by patent examiners) will be combined in any given year is increasing in the number of past combinations, decreasing over time, and increasing when both elements in the pair are also used with many other elements. These predictions are consistent with my model. The same work also predicts that patenting activity is positively correlated with changes in researcher knowledge about the connections between elements, and negatively correlated with time. Using panel data on 429 technology classes, I find the growth rate of patents is falling over time, but that increases can be forecast from positive changes in connections between elements 1-5 years earlier, even after controlling for numerous other factors. In my second paper, I examine the characteristics of the optimal research strategy for a forward-looking researcher using the above framework. To characterize the optimal strategy, I examine two special cases that permit analytic solutions, as well as a set of 100 numerically solved cases. The optimal research strategy reproduces many stylized facts about the innovation process, including the initial dominance of applied research relative to basic research. The third paper of my dissertation examines the impact of environmental policy choice on innovation, when research is characterized by unobservable (to the policy-maker) variance in technological opportunity. I assume there exist two types of energy, clean and dirty, that are perfect substitutes but for their production costs and a negative externality from dirty energy. Innovators are expected profit maximizers, and their decision to expend resources on R&D depends on technological opportunity, as well as the policy of the government. We show the policy-maker’s decision to use quota or price based incentives matters. Price based incentives such as a carbon tax are characterized by disperse outcomes, with more R&D resources expended when technological opportunity is high, and reduced amounts when technological opportunity is low. Quotas such as mandates, in contrast, lead to a more consistent level of R&D spending across differences in technological opportunity. Thus, price-based systems are more likely to deliver great technological advances or none at all, while mandates are more likely to deliver consistent incremental gains. Moreover, we also show an optimal carbon tax is likely to outperform any mandate in expected welfare terms, and has less information requirements

Mandates and the Incentive for Environmental Innovation

Mandates are policy tools that are becoming increasingly popular to promote renewable energy use. In addition to mitigating the pollution externality of conventional energy, mandates have the potential to promote R&D investments in renewable energy technology. But how well do mandates perform as innovation incentives? To address this question, we develop a partial equilibrium model with endogenous innovation to examine the R&D incentives induced by a mandate, and compare this policy to two benchmark situations: laissez-faire and a carbon tax. Innovation is stochastic and the model permits an endogenous number of multiple innovators. We find that mandates can improve upon laissez faire, and that the prospect of innovation is essential for their desirability. However, mandates suffer from several limitations. A mandate creates relatively strong incentives for investment in R&D in low-quality innovations, but relatively weak incentives to invest in high-quality innovations, so that the dispersion of realized innovation quality is comparatively low. Moreover, a mandate achieves lower welfare than a carbon tax, and its optimal level is more sensitive to the structure of the innovation process

Intellectual Property Rights and the Ascent of Proprietary Innovation in Agriculture

Biological innovations in agriculture did not enjoy protection by formal intellectual property rights (IPRs) for a long time, but the recent trend has been one of considerable broadening and strengthening of these rights. We document the nature of these IPRs and their evolution, and provide an assessment of their impacts on innovation. We integrate elements of the institutional history of plant IPRs with a discussion of the relevant economic theory and a review of applicable empirical evidence. Throughout, we highlight how the experience of biological innovation mirrors, or differs from, the broader literature on IPRs and innovation. We conclude with some considerations on the relation between IPRs and market structure and the pricing of proprietary inputs in agricultur

A Universal Next-Generation Sequencing Protocol To Generate Noninfectious Barcoded cDNA Libraries from High-Containment RNA Viruses

ABSTRACT Several biosafety level 3 and/or 4 (BSL-3/4) pathogens are high-consequence, single-stranded RNA viruses, and their genomes, when introduced into permissive cells, are infectious. Moreover, many of these viruses are select agents (SAs), and their genomes are also considered SAs. For this reason, cDNAs and/or their derivatives must be tested to ensure the absence of infectious virus and/or viral RNA before transfer out of the BSL-3/4 and/or SA laboratory. This tremendously limits the capacity to conduct viral genomic research, particularly the application of next-generation sequencing (NGS). Here, we present a sequence-independent method to rapidly amplify viral genomic RNA while simultaneously abolishing both viral and genomic RNA infectivity across multiple single-stranded positive-sense RNA (ssRNA+) virus families. The process generates barcoded DNA amplicons that range in length from 300 to 1,000 bp, which cannot be used to rescue a virus and are stable to transport at room temperature. Our barcoding approach allows for up to 288 barcoded samples to be pooled into a single library and run across various NGS platforms without potential reconstitution of the viral genome. Our data demonstrate that this approach provides full-length genomic sequence information not only from high-titer virion preparations but it can also recover specific viral sequence from samples with limited starting material in the background of cellular RNA, and it can be used to identify pathogens from unknown samples. In summary, we describe a rapid, universal standard operating procedure that generates high-quality NGS libraries free of infectious virus and infectious viral RNA. IMPORTANCE This report establishes and validates a standard operating procedure (SOP) for select agents (SAs) and other biosafety level 3 and/or 4 (BSL-3/4) RNA viruses to rapidly generate noninfectious, barcoded cDNA amenable for next-generation sequencing (NGS). This eliminates the burden of testing all processed samples derived from high-consequence pathogens prior to transfer from high-containment laboratories to lower-containment facilities for sequencing. Our established protocol can be scaled up for high-throughput sequencing of hundreds of samples simultaneously, which can dramatically reduce the cost and effort required for NGS library construction. NGS data from this SOP can provide complete genome coverage from viral stocks and can also detect virus-specific reads from limited starting material. Our data suggest that the procedure can be implemented and easily validated by institutional biosafety committees across research laboratories

Whole exome sequencing of circulating tumor cells provides a window into metastatic prostate cancer

Comprehensive analyses of cancer genomes promise to inform prognoses and precise cancer treatments. A major barrier, however, is inaccessibility of metastatic tissue. A potential solution is to characterize circulating tumor cells (CTCs), but this requires overcoming the challenges of isolating rare cells and sequencing low-input material. Here we report an integrated process to isolate, qualify and sequence whole exomes of CTCs with high fidelity, using a census-based sequencing strategy. Power calculations suggest that mapping of >99.995% of the standard exome is possible in CTCs. We validated our process in two prostate cancer patients including one for whom we sequenced CTCs, a lymph node metastasis and nine cores of the primary tumor. Fifty-one of 73 CTC mutations (70%) were observed in matched tissue. Moreover, we identified 10 early-trunk and 56 metastatic-trunk mutations in the non-CTC tumor samples and found 90% and 73% of these, respectively, in CTC exomes. This study establishes a foundation for CTC genomics in the clinic

The Main Belt Comets and ice in the Solar System

We review the evidence for buried ice in the asteroid belt; specifically the questions around the so-called Main Belt Comets (MBCs). We summarise the evidence for water throughout the Solar System, and describe the various methods for detecting it, including remote sensing from ultraviolet to radio wavelengths. We review progress in the first decade of study of MBCs, including observations, modelling of ice survival, and discussion on their origins. We then look at which methods will likely be most effective for further progress, including the key challenge of direct detection of (escaping) water in these bodies

Post-release reforms for short prison sentences: re-legitimising and widening the net of punishment

Transforming Rehabilitation (TR) promised a ‘revolution’ in the way offenders are managed, providing a renewed focus on short sentence prisoners. The TR reforms extends mandatory post-release supervision and tailored through-the-gate resettlement provisions to a group that has predominately faced a ‘history of neglect’ yet often present with the most acute needs within the criminal justice system. However, existing literature underlines that serving short sentences lack ‘utility’ and can be counter-productive to facilitating effective rehabilitation. This article explores the purposes of providing post release supervision for short sentences, firstly exploring a previous attempt to reform short sentences; (the now defunct) ‘Custody Plus’ within the 2003 Criminal Justice Act and then the Offender Rehabilitation Act 2014 within the TR reforms. This article contends that both post release reforms have sought to re-affirm and re-legitimise prison as the dominant form of punishment in society- or what Carlen refers to as ‘carceral clawback’. This article will also use Cohen’s analysis on social control to establish that post release supervision will serve to ‘widen the net’ extend the period of punishment and oversight and will only reinforce a form of enforced ‘state obligated rehabilitation’ that will undermine efforts made to resettle short sentence prisoners

Serological Profiling of a Candida albicans Protein Microarray Reveals Permanent Host-Pathogen Interplay and Stage-Specific Responses during Candidemia

Candida albicans in the immunocompetent host is a benign member of the human microbiota. Though, when host physiology is disrupted, this commensal-host interaction can degenerate and lead to an opportunistic infection. Relatively little is known regarding the dynamics of C. albicans colonization and pathogenesis. We developed a C. albicans cell surface protein microarray to profile the immunoglobulin G response during commensal colonization and candidemia. The antibody response from the sera of patients with candidemia and our negative control groups indicate that the immunocompetent host exists in permanent host-pathogen interplay with commensal C. albicans. This report also identifies cell surface antigens that are specific to different phases (i.e. acute, early and mid convalescence) of candidemia. We identified a set of thirteen cell surface antigens capable of distinguishing acute candidemia from healthy individuals and uninfected hospital patients with commensal colonization. Interestingly, a large proportion of these cell surface antigens are involved in either oxidative stress or drug resistance. In addition, we identified 33 antigenic proteins that are enriched in convalescent sera of the candidemia patients. Intriguingly, we found within this subset an increase in antigens associated with heme-associated iron acquisition. These findings have important implications for the mechanisms of C. albicans colonization as well as the development of systemic infection