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.
Stephen Jay Gould studied snail fossils and worked at Harvard University in Cambridge, Massachusetts during the latter half of the twentieth century. He contributed to philosophical, historical, and scientific ideas in paleontology, evolutionary theory, and developmental biology. Gould, with Niles Eldredge, proposed the theory of punctuated equilibrium, a view of evolution by which species undergo long periods of stasis followed by rapid changes over relatively short periods instead of continually accumulating slow changes over millions of years. In his 1977 book, Ontogeny and Phylogeny, Gould reconstructed a history of developmental biology and stressed the importance of development to evolutionary biology. In a 1979 paper coauthored with Richard Lewontin, Gould and Lewonitn criticized many evolutionary bioligists for relying solely on adaptive evolution as an explanation for morphological change, and for failing to consider other explanations, such as developmental constraints.
Aristotle studied developing organisms, among other things, in ancient Greece, and his writings shaped Western philosophy and natural science for greater than two thousand years. He spent much of his life in Greece and studied with Plato at Plato's Academy in Athens, where he later established his own school called the Lyceum. Aristotle wrote greater than 150 treatises on subjects ranging from aesthetics, politics, ethics, and natural philosophy, which include physics and biology. Less than fifty of Aristotle's treatises persisted into the twenty-first century. In natural philosophy, later called natural science, Aristotle established methods for investigation and reasoning and provided a theory on how embryos generate and develop. He originated the theory that an organism develops gradually from undifferentiated material, later called epigenesis.
David Starr Jordan studied fish and promoted eugenics in the US during the late nineteenth and early twentieth centuries. In his work, he embraced Charles Darwin s theory of evolution and described the importance of embryology in tracing phylogenic relationships. In 1891, he became the president of Stanford University in Stanford, California. Jordan condemned war and promoted conservationist causes for the California wilderness, and he advocated for the eugenic sterilization of thousands of Americans. Like many American eugenicists of the early twentieth century, Jordan combined ideas of Mendelian genetics and of Darwinian natural selection to form a basis for limiting or encouraging reproduction in certain individuals and groups based on their perceived hereditary fitness. Like other eugenicists, Jordan s attempt to control the reproductive fate of entire populations marked an episode in the history of reproduction and biology in which its concepts increasingly influenced the social and cultural contexts.
In 1928 Ezra Seymour Gosney founded the non-profit Human Betterment Foundation (HBF) in Pasadena, California to support the research and publication of the personal and social effects of eugenic sterilizations carried out in California. Led by director Gosney and secretary Paul Popenoe, the HBF collected data on thousands of individuals in California who had been involuntarily sterilized under a California state law enacted in 1909. The Foundation's assets were liquidated following Gosney's death in 1942. In 1943, Gosney's daughter donated the remaining assets to the California Institute of Technology (Caltech) in Pasadena, California to establish the Gosney research fund for biological research. Between 1928 and 1942, the HBF published extensively on what they believed to be the benefits of sterilization to both patient and society. The HBF and its members existed within the larger context of the American eugenics movement and scientific institutions, including the Eugenics Record Office at Cold Spring Harbor Laboratory in Cold Spring Harbor, New York, which bolstered the movement's goals of the control of human reproduction and human heredity. Moreover, the model sterilization legislation written by the HBF was disseminated throughout the world to eugenics enthusiasts eager to pass laws limiting the reproduction of people they considered to be unfit.
Georges Cuvier, baptized Georges Jean-Leopold Nicolas-Frederic Cuvier, was a professor of anatomy at the National Museum of Natural History in Paris, France, through the late eighteenth and early nineteenth centuries. Scholars recognize Cuvier as a founder of modern comparative anatomy, and as an important contributor to vertebrate paleontology and geology. Cuvier studied the form and function of animal anatomy, writing four volumes on quadruped fossils and co-writing eleven volumes on the natural history of fish with Achille Valenciennes. Moreover, Cuvier constructed a system of classification based on specific and well-articulated principles to help anatomists classify animal taxa. Cuvier had public debate in 1830 with Etienne Geoffroy Saint-Hilaire, a dispute centered on whether form or function matters most for the study of anatomy and whether the transmutation of organic forms can occur over time. Cuvier's opinions influenced the development of biology in France, and his arguments against transmutation of types influenced the reception of Charles Darwin's theory of evolution by natural selection among many French naturalists.