Computational Challenges of Personal Genomics

It is widely predicted that cost and efficiency gains in sequencing will usher in an era of personal genomics and personalized, predictive, preventive, and participatory medicine within a decade. I review the computational challenges ahead and propose general and specific directions for research and development. There is an urgent need to develop semantic ontologies that span genomics, molecular systems biology, and medical data. Although the development of such ontologies would be costly and difficult, the benefits will far outweigh the costs. I argue that availability of such ontologies would allow a revolution in web-services for personal genomics and medicine.     

Sir John Gurdon: Father of nuclear reprogramming

Sir John Gurdon founded the field of nuclear reprogramming. His work set the stage for the ever burgeoning area of stem cell biology and regenerative medicine. Here I provide personal reflections on times I shared with John Gurdon and professional reflections of the impact of his ground-breaking research on my own development as a scientist and on the field in general. His paradigm-shifting experiments will continue to provoke scientists to think outside the box for many years to come.     

Conscientious objection in healthcare: How much discretionary space best supports good medicine?

Daniel Sulmasy has recently argued that good medicine depends on physicians having a wide discretionary space in which they can act on their consciences. The only constraints Sulmasy believes we should place on physicians’ discretionary space are those defined by a form of tolerance he derives from Locke, whereby people can publicly act in accordance with their personal religious and moral beliefs as long as their actions are not destructive to society. Sulmasy also claims that those who would reject physicians’ right to conscientious objection eliminate discretionary space, thus undermining good medicine and unnecessarily limiting religious freedom. I argue that, although Sulmasy is correct that some discretionary space is necessary for good medicine, he is wrong in thinking that proscribing conscientious objection entails eliminating discretionary space. I illustrate this using Julian Savulescu and Udo Schuklenk’s system for restricting conscientious objections as a counter‐example. I then argue that a narrow discretionary space constrained by professional ideals will promote good medicine better than Sulmasy’s wider discretionary space constrained by his conception of tolerance. Sulmasy’s version of discretionary space would have us tolerate actions that are at odds with aspects of good medicine, including aspects that Sulmasy himself explicitly values, such as fiduciary duty. Therefore, if we want the degree of religious freedom in the public sphere that Sulmasy favours then we must decide whether it is worth the cost to the healthcare system.     

Personalisierte Medizin durch individuelle Genome

Recent advances in sequencing technology have reduced the costs and time required to decode a single genome to the extent that complete sequencing of personal genomes becomes affordable for both private individuals and the health care system. The broad availability of individual genomes will drive medicine further towards an information-based science and the importance of IT solutions in medicine will increase.     

Road-maps and revelations: on the somatic ethics of genetic susceptibility

Understanding genomic susceptibility risk has been represented as key to a new era of personalized medicine, in which “empowered” individuals shape their lives according to a “somatic ethics” of genetic risk management. Based on a comprehensive analysis of websites and other documents produced by key companies within the personal genomics industry, I argue that the rhetoric of empowerment these companies employ constructs an “ideal subject” of personal genomics while also expressing tensions implicit within the idea of a somatic ethics based on genetic susceptibility. Using Kaushik Sunder Rajan's concept of “genomic fetishism,” I show how these tensions arise from the relationship the rhetoric of personal genomics constructs between risk and uncertainty, and relate them to broader tensions within “risk thinking” as a mode of governmentality that extends beyond genomics.     

Gene targeting in mice: functional analysis of the mammalian genome for the twenty-first century

Gene targeting in mouse embryonic stem cells has become the 'gold standard' for determining gene function in mammals. Since its inception, this technology has revolutionized the study of mammalian biology and human medicine. Here I provide a personal account of the work that led to the generation of gene targeting which now lies at the centre of functional genomic analysis.     

The roots of bioinformatics in theoretical biology

From the late 1980s onward, the term "bioinformatics" mostly has been used to refer to computational methods for comparative analysis of genome data. However, the term was originally more widely defined as the study of informatic processes in biotic systems. In this essay, I will trace this early history (from a personal point of view) and I will argue that the original meaning of the term is re-emerging.     

Linus Pauling and sickle cell disease

The 1949 paper by Linus Pauling et al. [Science 110 (1949) 543–548] describing the discovery of sickle cell anemia as the first molecular disease had a major impact on biology and medicine. Inspired by the scholarly works of John Edsall on the history of hemoglobin research, I present a brief retrospective analysis of Pauling's paper. This is followed by some personal recollections of Edsall and Pauling.     

Unanswered questions in ecology

This is very much a personal view of what I think are some of the most important unanswered questions in ecology. That is, these are the questions that I expect will be high on the research agenda over the coming century. The list is organized hierarchically, beginning with questions at the level of individual populations, and progressing through interacting populations to entire communities or ecosystems. I will try to guess both at possible advances in basic knowledge and at potential applications. The only thing that is certain about this view of the future is that much of it will surely turn out to be wrong, and many of the most interesting future developments will be quite unforeseen.     

Medicare, ethics, and reflexive longevity: governing time and treatment in an aging society

The clinical activities that constitute longevity making in the United States are perhaps the quintessential example of a dynamic modern temporality, characterized by the quest for risk reduction, the powerful progress narratives of science and medicine, and the personal responsibility of calculating the worth of more time in relation to medical options and age. This article explores how medicine materializes and problematizes time through a discussion of ethicality-in this case, the form of governance in which scientific evidence, Medicare policy and clinical knowledge and practice organize first, what becomes "thinkable" as the best medicine, and second, how that kind of understanding shapes a telos of living. Using liver disease and liver transplantation in the United States as my example, I explore the influence of Medicare coverage decisions on treatments, clinical standards, and ethical necessity. Reflexive longevity-a relentless future-thinking about life itself-is one feature of this ethicality.     

A Factor Analytic Approach to Seriation

Abstract

Seriation, a unidimensional ordering technique, is one of archaeology’s oldest and most useful tools. Its mathematical aspects have drawn the attention of mathematicians and statisticians in recent years, even as archaeologists themselves have begun to question its underlying assumptions. In this paper I describe some techniques appropriate at each step in the mathematical seriation problem: discovering trendsensitive variables and ordering items on the basis of these variables.     

Mean age of death and longevity for male scientists of different specialties

The article provides information on the mean age of death (MAD) for 54 256 men professionally involved in research work and assigned to one of the six categories, namely, physics, chemistry, medicine and biology, mathematics, economics, and humanities. In addition, the effect of teaching activity on MAD and longevity has been evaluated for scientists of different specialties. Special attention has been paid to the analysis of MAD of the deceased members of the Russian Academy of Sciences, including members of the USSR Academy of Sciences (1724–2013). The minimum MAD has been found for mathematicians (72.1 ± 0.21 years) and the maximum MAD for scientists in economics (74.6 ± 0.26 years). The relative number of surviving ≥90 years and ≥100 years is minimal for mathematicians (7.59 and 0.37%, respectively), whereas those numbers for economists reveal the maximum values (10.26 and 0.96%, respectively). Indicators of MAD and proportion of centenarians among the scientists who received public recognition strongly depend on the specialty. Similarly, the members of the Russian Academy of Sciences and the USSR Academy of Sciences have the highest MAD in economics (74.7 ± 1.05 years) and the lowest in mathematics (70.6 ± 0.74 years). MAD has proven to be 3.5 years higher for scientists involved in teaching at university or college compared to those who were not involved in teaching. In this case, the “gain” is significant, ranging from 3.1 years for economists and humanitarians to 4.9 years for mathematicians. The results of the study lead to the conclusion that intense scientific work contributes to an increase in life expectancy and longevity.     

Knot theory in understanding proteins

This paper aims to enthuse mathematicians, especially topologists, knot theorists and geometers to examine problems in the study of proteins. We have highlighted those advances and breakthroughs in knot theory that directly and indirectly help in understanding proteins. We have discussed the phenomena of knotting of protein backbone. This paper also provides a few open questions for knot theorists, the answers to which will help in further understanding of proteins.     

Coregulation mapping based on individual phenotypic variation in response to virus infection

Background

Biology is moving fast toward the virtuous circle of other disciplines: from data to quantitative modeling and back to data. Models are usually developed by mathematicians, physicists, and computer scientists to translate qualitative or semi-quantitative biological knowledge into a quantitative approach. To eliminate semantic confusion between biology and other disciplines, it is necessary to have a list of the most important and frequently used concepts coherently defined.

Results

We propose a novel paradigm for generating new concepts for an ontology, starting from model rather than developing a database. We apply that approach to generate concepts for cell and molecule interaction starting from an agent based model. This effort provides a solid infrastructure that is useful to overcome the semantic ambiguities that arise between biologists and mathematicians, physicists, and computer scientists, when they interact in a multidisciplinary field.

Conclusions

This effort represents the first attempt at linking molecule ontology with cell ontology, in IMGT-ONTOLOGY, the well established ontology in immunogenetics and immunoinformatics, and a paradigm for life science biology. With the increasing use of models in biology and medicine, the need to link different levels, from molecules to cells to tissues and organs, is increasingly important.     

(M,R)-systems, (P,M,C)-nets, hierarchical decay, and biological aging: reminiscences of Robert Rosen

I have the pleasure to present a number of personal experiences that I had with Robert Rosen, both as his student and as a research colleague, and I will describe how this affected my academic career over the past decades. As a matter of fact, Rosen's work with (M,R)-systems as well as his continuing mentorship guided me into my own research in gerontology and geriatrics. Amazingly, this still continues to affect my work in complexity theory after 30 years.     

Microparticles and nanoparticles for drug delivery

Particulate drug delivery systems have become important in experimental pharmaceutics and clinical medicine. The distinction is often made between micro- and nanoparticles, being particles with dimensions best described in micrometers and nanometers respectively. That size difference entails real differences at many levels, from formulation to in vivo usage. Here I will discuss those differences and provide examples of applications, for local and systemic drug delivery. I will outline a number of challenges of interest in particulate drug delivery.     

Medical professionalism: crossing a generational divide

A comprehensive discussion of professionalism in medicine must include its impact on successive generations of physicians. Fifty years ago, doctors acting professionally emphasized medicine as a calling and an ability to act as the authority for patients in crisis at home and in hospitals. Therapeutic options were limited relative to the modern era, and the laying on of hands was practiced as science and art. Today, doctors balance increasing demands on time and efficiency with the sense of primacy of patient care. Technological innovation and patients' increasing access to medical knowledge through varying media of inconsistent quality challenge physicians in novel ways. Fifty years in the future, doctors will have access to vast amounts of information through a multitude of noninvasive diagnostics. Progressively more personalized medicine should inspire doctors to become even more adept at communicating effectively with patients. Professionalism in medicine throughout these generations embodies similar fundamental behaviors, such as demonstrating compassion, respect, and humility; adhering to high ethical and moral standards; subordinating personal interest to that of others; and reflecting on actions and decisions. Despite the dynamic nature of the profession itself, the omnipresent need for such traits will define medical professionalism for decades to come.     

一种新的基于单碱基延伸的SNP芯片技术

单核苷酸多态性(Single nucleotide polymorphism, SNP)是人类基因组中最常见的一种变异, 与疾病易感性、药物代谢等有着密切的关系。已经建立了多种SNP检测技术并得到了应用。单碱基延伸(Single base extension, SBE)是常用的SNP分型技术之一。文章建立了SBE结合Zip-code芯片技术对SNP进行分型, 为个体化用药及临床诊断芯片的研究与开发提供技术和方法。     

Systems Approaches to Biology and Disease Enable Translational Systems Medicine

The development and application of systems strategies to biology and disease are transforming medical research and clinical practice in an unprecedented rate.In the foreseeable future,clinicians,medical researchers,and ultimately the consumers and patients will be increasingly equipped with a deluge of personal health information,e.g.,whole genome sequences,molecular profiling of diseased tissues,and periodic multi-analyte blood testing of biomarker panels for disease and wellness.The convergence of these practices will enable accurate prediction of disease susceptibility and early diagnosis for actionable preventive schema and personalized treatment regimes tailored to each individual.It will also entail proactive participation from all major stakeholders in the health care system.We are at the dawn of predictive,preventive,personalized,and participatory(P4) medicine,the fully implementation of which requires marrying basic and clinical researches through advanced systems thinking and the employment of high-throughput technologies in genomics,proteomics,nanofluidics,single-cell analysis,and computation strategies in a highly-orchestrated discipline we termed translational systems medicine.