Revolutionizing medicine in the 21(st) century through systems approaches

Personalized medicine is a term for a revolution in medicine that envisions the individual patient as the central focus of healthcare in the future. The term "personalized medicine", however, fails to reflect the enormous dimensionality of this new medicine that will be predictive, preventive, personalized, and participatory-a vision of medicine we have termed P4 medicine. This reflects a paradigm change in how medicine will be practiced that is revolutionary rather than evolutionary. P4 medicine arises from the confluence of a systems approach to medicine and from the digitalization of medicine that creates the large data sets necessary to deal with the complexities of disease. We predict that systems approaches will empower the transition from conventional reactive medical practice to a more proactive P4 medicine focused on wellness, and will reverse the escalating costs of drug development an will have enormous social and economic benefits. Our vision for P4 medicine in 10 years is that each patient will be associated with a virtual data cloud of billions of data points and that we will have the information technology for healthcare to reduce this enormous data dimensionality to simple hypotheses about health and/or disease for each individual. These data will be multi-scale across all levels of biological organization and extremely heterogeneous in type - this enormous amount of data represents a striking signal-to-noise (S/N) challenge. The key to dealing with this S/N challenge is to take a "holistic systems approach" to disease as we will discuss in this article.     

BeadArray-based solutions for enabling the promise of pharmacogenomics

A "one-size-fits-all" approach continues to characterize today's healthcare paradigm. But emergent rules, information, genomics tools, and economics are driving a fundamental and inevitable shift to a more personalized world of medicine. In this new world, the interests of insurers, regulators, suppliers, healthcare providers, and most important, patients, will have converged. The new goal will be the right treatment for the right individual at the right time. In this world, personalized medicine, through pharmacogenomics (PGx), will be the new healthcare paradigm. We will briefly examine healthcare trends and current opportunities for PGx development. We will then demonstrate how microarray technologies-among them bead-based approaches-have emerged as a key enabler for bringing home the promise of PGx.     

Should human germ line editing be allowed? Some suggestions on the basis of the existing regulatory framework

The application of genetic editing techniques for the prevention or cure of disease is a highly promising tool for the future of humanity. However, its implementation contains a number of ethical and legal challenges that should not be underestimated. On this basis, some sectors have already asked for a veto on any intervention that modifies the human germ line, while supporting somatic line editing. In this paper, I will support that this suggestion makes no sense at all, because the somatic/germ line disjunctive has no moral relevance and, therefore, it should not play any role in legal terms. I will provide a number of reasons to hold this assumption, such as the non‐sacred nature of the germ line, the difference between germ line and human genome modification, or the moral importance of the presence of a will to create modified descendants. While doing so, I will provide some examples of the different approaches to germ line editing adopted by different regulations so as to demonstrate that, contrary to what is sometimes stated, a general ban on this practice is not the rule, but the exception. Additionally, I will show how alternative options which currently exist, such as a selective ban based on criteria different to the germ line/somatic line distinction, match better with the need to conciliate research needs and legitimate ethical concerns. Finally, I will introduce some further suggestions to this same purpose.     

Use of antibodies to the lipopolysaccharide core region in the treatment of gram-negative sepsis and shock

In this paper we review evidence in favor of a protective role for antibodies directed at the lipopolysaccharide (LPS) core region of Gram-negative bacilli. It will be shown that, given the right animal model, polyclonal antisera raised against O-antigen lacking, rough mutant strains, can be shown to protect animals against lethal sepsis due to a variety a bacterial species. Evidence for a protective role obtained from clinical studies will also be discussed. It will be stressed how difficult it is to prove that the antibodies directed against the LPS-core, and not other proteins present in the polyclonal anti-rough strain antisera, were responsible for the observed protective effects. The solution to some of these problems is the production of monoclonal antibodies (Mabs). We will discuss the findings that purified anti-core Mabs may give false-positive outcomes of protection studies, due to the induction of tolerance by small amounts of contaminating endotoxin, present in the antibody preparation. The need to administer the Mab therapeutically instead of prophylactically to the test animals, will be stressed. It will be shown how we succeeded in determining the epitope-specificities of several anti-core antibodies. It will be shown also that use of Elisa alone for characterization of anti-core Mabs may lead to false conclusions concerning epitope specificities. We will prove that synthetic KDO-(=ketodeoxycctanate) and lipid A-containing antigens are indispensable tools for thorough characterization of Mabs. Using this methodology we were able to discriminate between specific antigen-antibody interactions, and the ability of some Mabs to bind “non-specifically” to hydrophobic surfaces. The relationship between epitope specificity and protective effects of anti-core Mabs will be described. Finally, we will demonstrate that a KDO-specific Mabs is capable of protecting mice against lethal sepsis; in other words, it will be shown conclusively that Mabs to defined epitopes in LPS core region are cross-protective.     

Structural genomics on the web

In this review we provide a brief guide to some of the resources and databases that can be used to locate information and aid research in the growing field of structural genomics. The review will provide examples, for less experienced users, of what can be achieved using a selection of the available sites. We hope that this will encourage you to use these sites to their full potential and whet your appetite to search for other related sites.     

Emergence in the central nervous system

“Emergence” is an idea that has received much attention in consciousness literature, but it is difficult to find characterizations of that concept which are both specific and useful. I will precisely define and characterize a type of epistemic (“weak”) emergence and show that it is a property of some neural circuits throughout the CNS, on micro-, meso- and macroscopic levels. I will argue that possession of this property can result in profoundly altered neural dynamics on multiple levels in cortex and other systems. I will first describe emergent neural entities (ENEs) abstractly. I will then show how ENEs function specifically and concretely, and demonstrate some implications of this type of emergence for the CNS.     

Cryopreservation and the age of the allotransplant

For centuries, reconstructive surgeons have restored form and function with autografts. These techniques are highly effective, but they are associated invariably with donor site morbidity. To avoid this, surgeons have long dreamed of using cadaveric sources for reconstructive material. However, allografts have two major limitations: rejection and limited donor tissue. In order to limit rejection, the allograft must be rendered more tolerable to the host or the host must be rendered more tolerant of the allograft. Both strategies have been used with considerable success in recent years. As understanding of the human immune response increases, clinical immunosuppressive regimens will undoubtedly become less morbid, and the indications for allotransplantation will broaden. This will place an even greater burden on the already small donor pool. One way to relieve this burden would be through the development of strategies for the long-term preservation of donated tissues and organs. Cryopreservation has been used clinically for decades, and recent advances in the field have allowed the preservation of an ever widening array of tissues and organs. As cold storage has been shown to reduce the antigenicity of parts, cryopreservation may actually serve to improve the survival rate of transplanted parts, as well as increase their availability. As the era of autotransplantation gives way to the age of allotransplantation, cryopreservation will play an increasingly important role.     

Cryopreservation and the age of the allotransplant

For centuries, reconstructive surgeons have restored form and function with autografts. These techniques are highly effective, but they are associated invariably with donor site morbidity. To avoid this, surgeons have long dreamed of using cadaveric sources for reconstructive material. However, allografts have two major limitations: rejection and limited donor tissue. In order to limit rejection, the allograft must be rendered more tolerable to the host or the host must be rendered more tolerant of the allograft. Both strategies have been used with considerable success in recent years. As understanding of the human immune response increases, clinical immunosuppressive regimens will undoubtedly become less morbid, and the indications for allotransplantation will broaden. This will place an even greater burden on the already small donor pool. One way to relieve this burden would be through the development of strategies for the long-term preservation of donated tissues and organs. Cryopreservation has been used clinically for decades, and recent advances in the field have allowed the preservation of an ever widening array of tissues and organs. As cold storage has been shown to reduce the antigenicity of parts, cryopreservation may actually serve to improve the survival rate of transplanted parts, as well as increase their availability. As the era of autotransplantation gives way to the age of allotransplantation, cryopreservation will play an increasingly important role.     

"Paleogenomics": looking in the past to the future

The complete sequence of the human and other vertebrate and nonvertebrate genomes provide a wealth of information on the organization, relationships and evolution of the metazoans. Soon the fine structure of our innermost biological identity will be unveiled and what has so far remained deep and secret will shine like an unearthed treasure and shape and fuel our future quests. A key treasure, for many molecular scientists interested in molecular evolution and development would be the knowledge of the genome of the ancestral precursor of all metazoans. In the absence of fossil DNA, this knowledge will forever remain a yearning for dreamy molecular biologists. And yet, will not the power of deduction and reconstitution of information gained through man's sophisticated technologies one day recreate a "virtual" metazoan ancestor?     

Live Imaging of Mitosis in the Developing Mouse Embryonic Cortex

Although of short duration, mitosis is a complex and dynamic multi-step process fundamental for development of organs including the brain. In the developing cerebral cortex, abnormal mitosis of neural progenitors can cause defects in brain size and function. Hence, there is a critical need for tools to understand the mechanisms of neural progenitor mitosis. Cortical development in rodents is an outstanding model for studying this process. Neural progenitor mitosis is commonly examined in fixed brain sections. This protocol will describe in detail an approach for live imaging of mitosis in ex vivo embryonic brain slices. We will describe the critical steps for this procedure, which include: brain extraction, brain embedding, vibratome sectioning of brain slices, staining and culturing of slices, and time-lapse imaging. We will then demonstrate and describe in detail how to perform post-acquisition analysis of mitosis. We include representative results from this assay using the vital dye Syto11, transgenic mice (histone H2B-EGFP and centrin-EGFP), and in utero electroporation (mCherry-α-tubulin). We will discuss how this procedure can be best optimized and how it can be modified for study of genetic regulation of mitosis. Live imaging of mitosis in brain slices is a flexible approach to assess the impact of age, anatomy, and genetic perturbation in a controlled environment, and to generate a large amount of data with high temporal and spatial resolution. Hence this protocol will complement existing tools for analysis of neural progenitor mitosis.     

Strategies for the genetic manipulation of Saccharomyces cerevisiae.

The budding yeast Saccharomyces cerevisiae is now widely used as a model organism in the study of gene structure, function, and regulation in addition to its more traditional use as a workhorse of the brewing and baking industries. In this article the plethora of methods available for manipulating the genome of S. cerevisiae are reviewed. This will include a discussion of methods for manipulating individual genes and whole chromosomes, and will address both classic genetic and recombinant DNA-based methods. Furthermore, a critical evaluation of the various genetic strategies for genetically manipulating this simple eukaryote will be included, highlighting the requirements of both the new and the more traditional biotechnology industries.     

Governing UK Biobank: the importance of ensuring public trust

In the autumn of 2003, UK Biobank published the first draft of its Ethics and Governance Framework. Subsequently, this document has been available for interested parties to comment on and the UK Biobank Board of Directors is expected to adopt the final version in 2004. Here, we aim to contribute to this process and highlight to a wider audience some of the inconsistencies in the issues of consent, governance and right of withdrawal that emerge from the draft of the Framework. These issues will have implications for securing the public trust and long-term support that the success of the project depends on. Therefore, they must be considered carefully because the UK Biobank will be the first ever genetic database of a general population of this size to become operational, and will be used as a model for other projects of this kind.     

On the challenges of detecting whole Staphylococcus aureus cells with biosensors

Due to the increasing number of nosocomial infections and multidrug‐resistant bacterial strains, Staphylococcus aureus is now a major worldwide concern. Rapid detection and characterization of this bacterium has become an important issue for biomedical applications. Biosensors are increasingly appearing as low‐cost, easy‐to‐operate and fast alternatives for rapid detection. In this review, we will introduce the main characteristics of S. aureus and will focus on the interest of biosensors for a faster detection of whole S. aureus cells. In particular, we will review the most promising strategies in the choice of ligand for the design of selective and efficient biosensors. Their specific characteristics as well as their advantages and/or disadvantages will also be commented.     

Weeding out the genes: the Arabidopsis genome project

The Arabidopsis genome sequence is scheduled for completion at the end of this year (December 2000). It will be the first higher plant genome to be sequenced, and will allow a detailed comparison with bacterial, yeast and animal genomes. Already, two of the five chromosomes have been sequenced, and we have had our first glimpse of higher eukaryotic centromeres, and the structure of heterochromatin. The implications for understanding plant gene function, genome structure and genome organization are profound. In this review, the lessons learned for future genome projects are reviewed as well as a summary of the initial findings in Arabidopsis. Electronic Publication     

Microbial biosorption of metals: potential in the treatment of metal pollution

The phenomenon of metal biosorption by microorganisms has been thoroughly documented. Although this phenomenon is exhibited by both living and non-living forms of biomass, the purpose of this chapter will be to review biosorption by the latter. In addition, the application of various technological processes required for exploitation of this phenomenon in waste treatment will be examined.     

板皮形状与尺寸的数学描述理论

本文为制材、剩余物利用等行业需要的板皮数控加工提供数学描述理论,提出的这些理论将为板皮裁边的数控加工数学模型建立提供编程的数学方程,为板材最优下锯的视频再现提供数学方法.本文提出的理论还将为锯切、板皮材积精确检测提供理论依据,与制材工艺结合起来,将使传统加工工艺数学化,为科学管理和数字化控制提供了理论.本文是木材工业中用板皮数学描述加工过程的开始.通过本文的研究,可以推进木材工业加工过程数学描述研究的开展.     

Use of an individual-based model to forecast the effect of climate change on the dynamics, abundance and geographical range of the pest slug Deroceras reticulatum in the UK

Slugs are serious agricultural pests and their activity is strongly driven by ambient temperature and soil moisture. The strength of this relationship has been shown through the development of a deterministic model, based upon temperature and soil moisture conditions alone, which accurately describes the population dynamics and abundance of Deroceras reticulatum . Because of this strong climatic dependence, slug abundance and dynamics are likely to be affected by climate change. We used a validated individual-based model (IbM) of D. reticulatum , to assess the effects of climate change on the abundance of this species in the UK. Climatic scenarios were based on the UKCIP02 predictions and constructed using the LARS-WG stochastic weather generator. The IbM of slugs predicted population dynamics at three time slices (2020s, 2050s and 2080s), and two scenarios of greenhouse gas emissions. The maximum generation number, the number of population peaks, the number of slug-days in each season, the percentage of years when the population passes over a threshold for damage and the percentage of years in which populations go extinct were investigated. Currently, the south-west of the UK has the best conditions for D. reticulatum to thrive, with the north-east of Scotland having the most adverse. By 2080 under both low- and high-emissions scenarios, the north and west of Scotland will have the most favourable conditions for the survival of this species and the east of the UK and Scotland will have the harshest. By 2080 the climate in the north-west of Scotland will become more like the current climate in south-east England, which explains the shift in the pattern of abundance. The north-west of Scotland will have increased slug damage and south-west England and west-Wales will have decreased slug damage with some changes becoming evident by 2020.     

Ensuring the security of synthetic biology—towards a 5P governance strategy

Over recent years the label “synthetic biology” has been attached to a number of diverse research and commercial activities, ranging from the search for a minimal cell to the quick delivery of customized genes by DNA synthesis companies. Based on the analysis of biosecurity issues surrounding synthetic biology during the SYNBIOSAFE project, this paper will first provide a rationale for taking security, in addition to safety aspects of this new field, seriously. It will then take stock of the initiatives and measures that have already been taken in this area and will lastly try to map out future areas of activities in order to minimise the security risks emanating from this promising new field of scientific inquiry and technological progress.     

On the computational architecture of the neocortex

This paper proposes that each area of the cortex carries on its calculations with the active participation of a nucleus in the thalamus with which it is reciprocally and topographically connected. Each cortical area is responsible for maintaining and updating the organism's knowledge of a specific aspect of the world, ranging from low level raw data to high level abstract representations, and involving interpreting stimuli and generating actions. In doing this, it will draw on multiple sources of expertise, learned from experience, creating multiple, often conflicting, hypotheses which are integrated by the action of the thalamic neurons and then sent back to the standard input layer of the cortex. Thus this nucleus plays the role of an 'active blackboard' on which the current best reconstruction of some aspect of the world is always displayed. Evidence for this theory is reviewed and experimental tests are proposed. A sequel to this paper will discuss the cortico-cortical loops and propose quite different computational roles for them.