Biology by Design: From Top to Bottom and Back

Synthetic biology is a nascent technical discipline that seeks to enable the design and construction of novel biological systems to meet pressing societal needs. However, engineering biology still requires much trial and error because we lack effective approaches for connecting basic “parts” into higher-order networks that behave as predicted. Developing strategies for improving the performance and sophistication of our designs is informed by two overarching perspectives: “bottom-up” and “top-down” considerations. Using this framework, we describe a conceptual model for developing novel biological systems that function and interact with existing biological components in a predictable fashion. We discuss this model in the context of three topical areas: biochemical transformations, cellular devices and therapeutics, and approaches that expand the chemistry of life. Ten years after the construction of synthetic biology's first devices, the drive to look beyond what does exist to what can exist is ushering in an era of biology by design

Tritium labeling of potential lipophilic myelin probes

Two potential lipophilic myelin imaging agents (1,1,2,2‐tetrafluoro‐1,2‐diphenylethane and 1‐fluoroadamantane) were tritium labeled. The most effective method employed the microwave discharge activation of tritium gas technique and resulted in specific activities of 177 mCi/mmol for 1,1,2,2‐tetrafluoro‐1,2‐diphenylethane and 593 mCi/mmol for 1‐fluoroadamantane. Using this tritiation method significant amounts of tritium‐for‐fluorine substitution was also observed in the labeling of 1‐fluoroadamatane, resulting in nearly equivalent amounts of tritiated adamantane and fluoroadamantane.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90398/1/2580210110_ftp.pd

Increased Lysis of Stem Cells but Not Their Differentiated Cells by Natural Killer Cells; De-Differentiation or Reprogramming Activates NK Cells

The aims of this study are to demonstrate the increased lysis of stem cells but not their differentiated counterparts by the NK cells and to determine whether disturbance in cell differentiation is a cause for increased sensitivity to NK cell mediated cytotoxicity. Increased cytotoxicity and augmented secretion of IFN-γ were both observed when PBMCs or NK cells were co-incubated with primary UCLA oral squamous carcinoma stem cells (UCLA-OSCSCs) when compared to differentiated UCLA oral squamous carcinoma cells (UCLA-OSCCs). In addition, human embryonic stem cells (hESCs) were also lysed greatly by the NK cells. Moreover, NK cells were found to lyse human Mesenchymal Stem Cells (hMSCs), human dental pulp stem cells (hDPSCs) and human induced pluripotent stem cells (hiPSCs) significantly more than their differentiated counterparts or parental lines from which they were derived. It was also found that inhibition of differentiation or reversion of cells to a less-differentiated phenotype by blocking NFκB or targeted knock down of COX2 in monocytes significantly augmented NK cell cytotoxicity and secretion of IFN-γ. Taken together, these results suggest that stem cells are significant targets of the NK cell cytotoxicity. However, to support differentiation of a subset of tumor or healthy untransformed primary stem cells, NK cells may be required to lyse a number of stem cells and/or those which are either defective or incapable of full differentiation in order to lose their cytotoxic function and gain the ability to secrete cytokines (split anergy). Therefore, patients with cancer may benefit from repeated allogeneic NK cell transplantation for specific elimination of cancer stem cells

PET scan investigations of Huntington's disease: Cerebral metabolic correlates of neurological features and functional decline

Fifteen drug-free patients with early to midstage Huntington's disease were evaluated with quantitative neurological examinations, scales for functional capacity, computed tomographic (CT) scans, and positron emission tomographic (PET) scans of 18 F-2-fluoro-2-deoxyglucose ( 18 F-FDG) uptake. All patients had abnormal indices of caudate metabolism on PET scanning, whereas in patients with early disease indices of putamen metabolism and CT measures of caudate atrophy were normal. Indices of caudate metabolism correlated highly with the patients' overall functional capacity ( r = 0.906; p < 0.001) and bradykinesia/rigidity ( r = −0.692; p < 0.01). Indices of putamen metabolism correlated highly with motor functions: Chorea ( r = −0.841; p < 0.01), oculomotor abnormalities ( r = −0.849; p < 0.01), and fine motor coordination ( r = −0.866; p < 0.01). Indices of thalamic metabolism correlated positively with dystonia ( r = 0.559; p < 0.05). The data suggest that PET scanning with 18 F-FDG is a sensitive measure of brain dysfunction in Huntington's disease and that basal ganglia metabolism is highly correlated with the overall functional capacity of individual patients and with the degree of their motor abnormalities.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/50317/1/410200305_ftp.pd