Recent transcriptome data from yeast, worm, plants, and humans has shown that alternative polyadenylation (APA), a mechanism that enables expression of multiple 3′UTR isoforms for the same gene, is widespread in eukaryotic organisms. It is still poorly understood why metazoans require multiple 3′UTRs for the same gene, but accumulating evidence suggests that APA is largely regulated at a tissue-specific level. APA may direct combinatorial variation between cis-elements and microRNAs, perhaps to regulate gene expression in a tissue-specific manner. Apart from a few single gene anecdotes, this idea has not been systematically explored.
This dissertation research employs a systems biology approach to study the somatic tissue dynamics of APA and its impact on microRNA targeting networks in the small nematode C. elegans. In the first aim, tools were developed and applied to isolate and sequence mRNA from worm intestine and muscle tissues, which revealed pervasive tissue-specific APA correlated with microRNA regulation. The second aim provides genetic evidence that two worm genes use APA to escape repression by microRNAs in the body muscle. Finally, in aim three, mRNA from five additional somatic worm tissues was sequenced and their 3′ends mapped, allowing for an integrative study of APA and microRNA targeting dynamics in worms. Together, this work provides evidence that APA is a pervasive mechanism operating in somatic tissues of C. elegans with the potential to significantly rearrange their microRNA regulatory networks and precisely dose their gene expression.
This project utilized computational tools to analyze large data sets and interpreted the results from historical and philosophical perspectives. Tools deployed were derived from scientometrics, corpus linguistics, text-based analysis, network analysis, and GIS analysis to analyze more than 9000 articles (metadata and text) on systems biology. The application of these tools to a HPS project represents a novel approach.
The dissertation shows that systems biology has transitioned from a more mathematical, computational, and engineering-oriented discipline focusing on modeling to a more biology-oriented discipline that uses modeling as a means to address real biological problems. Also, the results show that bioengineering and medical research has increased within systems biology. This is reflected in the increase of the centrality of biology-related concepts such as cancer, over time. The dissertation also compares the development of systems biology in China with some other parts of the world, and reveals regional differences, such as a unique trajectory of systems biology in China related to a focus on traditional Chinese medicine.
This dissertation adds to the historiography of modern biology where few studies have focused on systems biology compared with the history of molecular biology and evolutionary biology.
The first chapter revisits some of the key experiments that contributed to the development of the repression model of genetic regulation in the lac operon and concludes that the early research on gene expression and genetic regulation depict an iterative and integrative process, which was neither reductionist nor holist. In doing so, it challenges a common application of a conceptual framework in the history of biology and offers an alternative framework. The second chapter argues that the concept of emergence in the history and philosophy of biology is too ambiguous to account for the current research in post-genomic molecular biology and it is often erroneously used to argue against some reductionist theses. The third chapter investigates the use of network representations of gene expression in developmental evolution research and takes up some of the conceptual and methodological problems it has generated. The concluding comments present potential avenues for future research arising from each substantial chapter.
In sum, this dissertation argues that the epistemic practices of gene expression research are an iterative and integrative process, which produces theoretical representations of the complex interactions in gene expression as networks. Moreover, conceptualizing these interactions as networks constrains empirical research strategies by the limited number of ways in which gene expression can be controlled through general rules of network interactions. Making these strategies explicit helps to clarify how they can explain the dynamic and adaptive features of genomes.
In 1868 in England, Charles Darwin proposed his pangenesis theory to describe the units of inheritance between parents and offspring and the processes by which those units control development in offspring. Darwin coined the concept of gemmules, which he said referred to hypothesized minute particles of inheritance thrown off by all cells of the body. The theory suggested that an organism's environment could modify the gemmules in any parts of the body, and that these modified gemmules would congregate in the reproductive organs of parents to be passed on to their offspring. Darwin's theory of pangenesis gradually lost popularity in the 1890s when biologists increasingly abandoned the theory of inheritance of acquired characteristics (IAC), on which the pangenesis theory partially relied. Around the turn of the twentieth century, biologists replaced the theory of pangenesis with germ plasm theory and then with chromosomal theories of inheritance, and they replaced the concept of gemmules with that of genes.
Green fluorescent protein (GFP) is a protein in the jellyfish Aequorea Victoria that exhibits green fluorescence when exposed to light. The protein has 238 amino acids, three of them (Numbers 65 to 67) form a structure that emits visible green fluorescent light. In the jellyfish, GFP interacts with another protein, called aequorin, which emits blue light when added with calcium. Biologists use GFP to study cells in embryos and fetuses during developmental processes.
Golden Rice was engineered from normal rice by Ingo Potrykus and Peter Beyer in the 1990s to help improve human health. Golden Rice has an engineered multi-gene biochemical pathway in its genome. This pathway produces beta-carotene, a molecule that becomes vitamin A when metabolized by humans. Ingo Potrykus worked at the Swiss Federal Institute of Technology in Zurich, Switzerland, and Peter Beyer worked at University of Freiburg, in Freiburg, Germany. The US Rockefeller Foundation supported their collaboration. The scientists and their collaborators first succeeded in expressing beta-carotene in rice in 1999, and they published the results in 2000. Since then, scientists have improved Golden Rice through laboratory and field trials, but as of 2013 no countries have grown it commercially. Golden Rice is a technology that intersects scientific and ethical debates that extend beyond a grain of rice.
Friedrich Leopold August Weismann published Das
Keimplasma: eine Theorie der Vererbung (The Germ-Plasm: a
Theory of Heredity, hereafter The Germ-Plasm) while
working at the University of Freiburg in Freiburg, Germany in 1892.
William N. Parker, a professor in the University College of South
Wales and Monmouthshire in Cardiff, UK, translated The
Germ-Plasm into English in 1893. In The Germ-Plasm,
Weismann proposed a theory of heredity based on the concept of the
germ plasm, a substance in the germ cell that carries hereditary information. The
Germ-Plasm compiled Weismann's theoretical work and analyses of
other biologists' experimental work in the 1880s, and it provided a
framework to study development, evolution and heredity. Weismann
anticipated that the germ-plasm theory would enable researchers to
investigate the functions and material of hereditary substances.
Dell Publishing in New York City, New York, published Lennart Nilsson's A Child Is Born in 1966. The book was a translation of the Swedish version called Ett barn blir till, published in 1965. It sold over a million copies in its first edition, and has translations in twelve languages. Nilsson, a photojournalist, documented a nine-month human pregnancy using pictures and accompanying text written by doctors Axel Ingelman-Sundberg, Claes Wirsen and translated by Britt and Claes Wirsen and Annabelle MacMillian. Critics lauded A Child Is Born for its photographs taken in utero of a developing fetus. Furthermore, the work received additional praise for what many described as simple and scientifically accurate explanations of complicated processes during development.