The old man and the sea urchin genome: theory and data in the work of Eric Davidson, 1969-2006

Eric Davidson's work from 1969-2006 illustrates a period in the study of gene regulation that marked a transition from the gene to the genome and from theory-driven to data-intensive science. To make sense of this transition, I address Davidson's work during a first, predominantly theoretical, episode and contrast it with a later chapter in his research devoted to sequencing the California purple sea urchin genome and, more recently, to the computerized analysis of sea urchin development. By comparing these two approaches I offer some thoughts on how work configuration and material organization in the study of metazoan gene regulation have changed over the past forty years.     

Modeling disease in the mouse: lessons from DNA damage response and cell cycle control genes

The advent of gene targeting has allowed the dissection of many essential cellular pathways, including those involved in cell cycle regulation, signal transduction, and development. However, it is becoming increasingly clear that the simple gene deletion strategy may not be sufficient for the modeling of many cancer syndromes. In this Prospect article, we will discuss the strengths and weaknesses of mouse models, how they have advanced from gene deletions to truncations, point mutations, and conditional mouse models in which expression or loss of the gene of interest is controlled either temporally or spatially. We will also consider future directions for the use of mouse models in cancer. The vastness of the field necessitates focusing on a few specific examples with the unfortunate exclusion of many excellent studies from our discussion. As such, we focus on a few specific models of human cancer syndromes, however many of the themes discussed here are applicable to other systems of genetic manipulation and may be applied across fields.     

Induction of cell death by adenoviruses

Adenoviruses have proved to be excellent tools for gaining insight into the regulation, and deregulation, of the mammalian cell cycle. With the widespread clinical use of gene therapy fast approaching, there comes a need for a better understanding of how the cell death process is regulated. A greater understanding will allow the development of therapeutic approaches that both maximise transgene expression while minimising cytotoxicity to the target cell. Consequently, much adenovirus research has centered on understanding the mechanisms governing adenovirus induced cell death or apoptosis. This review discusses recent advances in the field of adenovirus cell death regulation and evaluates the roles of implicated gene products and their respective data. The data suggest the existence of multiple virus gene products involved in cell death regulation and point towards several distinct, yet related, cell death pathways. A discussion of the shortcomings of current adenoviral research, along with a proposed model based upon the data is also given.     

MicroRNAs and the Operon paper

The “Operon paper” by F. Jacob and J. Monod started 50 years of research into understanding how the expression of genes is regulated on a molecular level. Ten years ago, microRNAs (miRNAs) emerged as major regulators of eukaryotic gene expression. Here, I will review the basic principles of gene regulation by miRNAs and how these principles can be linked to insights from the Operon paper. A lot of what is understood about miRNAs required a combination of computational and experimental methods. I will discuss some examples that illustrate the power of this approach.     

Chromatin looping and the probability of transcription

Recent studies of several multigene clusters have shown that gene activation by a remote enhancer is associated with chromatin loop formation. It is not fully understood how a chromatin loop forms in a nucleus or how it is involved in gene regulation. In this article, we propose that the major feature that determines loop formation is the flexibility of chromatin, and that this flexibility is modulated by histone acetylation (and other modifications). Thus, histone modifications will modulate distribution of the preferential looping site in chromatin, which, in turn, determines the probability of interaction between a remote enhancer and the cognate genes. This model can explain gene expression changes in the Hoxd gene cluster and the beta-globin locus.     

GENETIC HARM: BITTEN BY THE BODY THAT KEEPS YOU?

... We must attempt to explain, how, if ever, our existence may harm us. To address this and the other questions raised, I propose to examine what constitutes harm and whether it makes sense to say that our genetic makeup may harm us. To do this I will describe three approaches to the problem of describing the status of negative effects our genes have upon us, which I have named the "technical harm" view, the "constitutive" view, and the "harmful conditions" view. On the technical harm view, the standard definitions of harm are applied to genetic disposition in an attempt to couch genetic defects or flaws in terms of harming. The constitutive view rejects applying the concept of harm to genetic disposition on the grounds that it is impossible to separate genetic disposition from individual identity. Lastly, the harmful conditions view, which I conclude is the most successful of the three, focuses on the tendency of certain genetic dispositions to cause harm in the future and thus avoids what I will argue are the "context" shortcomings of the other two approaches. To conclude the discussion I will very briefly analyze the ramifications of a harmful conditions view for the concept of genetic disease and the prospects for genetic counseling, gene therapy, and reproductive decision making.     

An historical-physiological analysis of the discussion between I. P. Pavlov and V. M. Bekhterev on the problems of localizing functions in the cerebral cortex

This article is the first of the domestic publications on physiology and medical history, which highlights the discussion between I. P. Pavlov and V. M. Bekhterev on the issue of localization of functions in human cerebral cortex: it provides information of the visit by I. P. Pavlov to the clinic of V. M. Bekhterev; it discusses the role of V. M. Bekhrerev's students who described the cortex zones of tonotopics, gustation, regulation of salivation and stomach secretion, which I. P. Pavlov denied. Unlike articles on factography and history of physiology, which in various ways praise the scientists, this article is based of the modern approaches of medical history and scientific knowledge, in particular, it provides a retrospective of the major facts of the discussion.     

The operon as paradigm: normal science and the beginning of biological complexity

The papers from the Jacob and Monod groups that presented the operon model and repressor control of gene expression provided a paradigm that opened up the field of gene regulation. Following the set of papers published between 1958 and 1961, there ensued almost immediately a period of “normal science” as Thomas Kuhn has defined it. Most researchers applied the repressor model to their own systems. I suggest a number of factors that were responsible for the rapid acceptance of the Jacob-Monod model and inhibited suggestions for alternative mechanisms of regulation. Nevertheless, I argue that this adherence to the paradigm, including specifically control by repressors, may well have been necessary for the field to progress. Ultimately, the evolution of this field of study was to reveal the unexpected complexity to genetic regulation.     

Consequences of population topology for studying gene flow using link‐based landscape genetic methods

Many landscape genetic studies aim to determine the effect of landscape on gene flow between populations. These studies frequently employ link‐based methods that relate pairwise measures of historical gene flow to measures of the landscape and the geographical distance between populations. However, apart from landscape and distance, there is a third important factor that can influence historical gene flow, that is, population topology (i.e., the arrangement of populations throughout a landscape). As the population topology is determined in part by the landscape configuration, I argue that it should play a more prominent role in landscape genetics. Making use of existing literature and theoretical examples, I discuss how population topology can influence results in landscape genetic studies and how it can be taken into account to improve the accuracy of these results. In support of my arguments, I have performed a literature review of landscape genetic studies published during the first half of 2015 as well as several computer simulations of gene flow between populations. First, I argue why one should carefully consider which population pairs should be included in link‐based analyses. Second, I discuss several ways in which the population topology can be incorporated in response and explanatory variables. Third, I outline why it is important to sample populations in such a way that a good representation of the population topology is obtained. Fourth, I discuss how statistical testing for link‐based approaches could be influenced by the population topology. I conclude the article with six recommendations geared toward better incorporating population topology in link‐based landscape genetic studies.     

Small RNA biology is systems biology

During the last decade small regulatory RNA (srRNA) emerged as central players in the regulation of gene expression in all kingdoms of life. Multiple pathways for srRNA biogenesis and diverse mechanisms of gene regulation may indicate that srRNA regulation evolved independently multiple times. However, small RNA pathways share numerous properties, including the ability of a single srRNA to regulate multiple targets. Some of the mechanisms of gene regulation by srRNAs have significant effect on the abundance of free srRNAs that are ready to interact with new targets. This results in indirect interactions among seemingly unrelated genes, as well as in a crosstalk between different srRNA pathways. Here we briefly review and compare the major srRNA pathways, and argue that the impact of srRNA is always at the system level. We demonstrate how a simple mathematical model can ease the discussion of governing principles. To demonstrate these points we review a few examples from bacteria and animals.     

Molecular epidemiology: potential impacts on the assessment of public health

In trying to decide what type of scientific paper I could prepare as a tribute to Jim Neel, I thought back over the discussions that we had over some 25 years. Sometimes these discussions were on specific topics such as how to extrapolate from mutation data in mice to those for humans following radiation or chemical exposures. On other occasions, our discussions were of a more philosophical nature, particularly on where the field of epidemiology might or needed to go. For example, what types of data are needed for assessing the public health impact of exposure to environmental agents. Perhaps because I enjoyed these discussions so much, I have chosen to take a look from a current perspective at the field of molecular epidemiology. Jim Neel would have loved to have entered into this discussion; he would have enhanced it in is own inimitable way.