Newtonianism and the enthusiasm of Enlightenment

The career of John Jackson (1686-1763), Arian theologian and controversialist, provides a key to unlocking the early reception and quick collapse of a Newtonian natural apologetic originally developed by Samuel Clarke. The importance of friendship and discipleship in eighteenth-century intellectual enquiry is emphasised, and the links between Newton and his followers are traced alongside those of a group of Cambridge Lockeans, led by Jackson’s direct contemporary Daniel Waterland, who proved instrumental in the initial dismantling of Clarke’s brand of Newtonian apologetic. The controversial context of this engagement is shown to have been largely provided by the religiously compromising rise of freethinking, and Tindal’s Christianity as old as the creation (1731) signalled the dangers to proponents of natural religion as an adjunct of Christian apologetic in such a heated atmosphere. Religious division of the sort that resulted paradoxically played into the hands of the freethinkers in the anticlerical atmosphere of the 1730s, and accusations were exchanged between Newtonians and Lockeans accordingly. The dynamic of England’s Enlightenment experience is, then, a complicated one, and, as the career and writings of Jackson and William Whiston demonstrate, it was one which absorbed as well as repudiated ‘enthusiasm’.     

Anthropologist fired: Stanford plays its China card

The ethical obligations of Western anthropologists working in the People's Republic of China became an issue recently when Stanford University's anthropology department unanimously decided to dismiss doctoral candidate Steven Mosher because of his conduct while in an unnamed Chinese village. Mosher maintains that the dismissal was in retaliation for his publishing an article in a Taiwanese weekly about the practices of forced third trimester abortion and infanticide in the village. Neither Stanford nor Mosher has revealed the specific reasons for the dismissal.     

Expected change: U.S. recombinant DNA guidelines

Continuing the trend towards relaxing controls on recombinant DNA research, the National Institutes of Health published revised guidelines in the Federal Register of 21 April 1982. Although the existing system of mandatory controls and institutional biosafety committees is retained, no class of experiments will be totally prohibited, and the guidelines dealing with containment levels have been greatly simplified.     

HDAC6 rescues neurodegeneration and provides an essential link between autophagy and the UPS

A prominent feature of late-onset neurodegenerative diseases is accumulation of misfolded protein in vulnerable neurons. When levels of misfolded protein overwhelm degradative pathways, the result is cellular toxicity and neurodegeneration. Cellular mechanisms for degrading misfolded protein include the ubiquitin-proteasome system (UPS), the main non-lysosomal degradative pathway for ubiquitinated proteins, and autophagy, a lysosome-mediated degradative pathway. The UPS and autophagy have long been viewed as complementary degradation systems with no point of intersection. This view has been challenged by two observations suggesting an apparent interaction: impairment of the UPS induces autophagy in vitro, and conditional knockout of autophagy in the mouse brain leads to neurodegeneration with ubiquitin-positive pathology. It is not known whether autophagy is strictly a parallel degradation system, or whether it is a compensatory degradation system when the UPS is impaired; furthermore, if there is a compensatory interaction between these systems, the molecular link is not known. Here we show that autophagy acts as a compensatory degradation system when the UPS is impaired in Drosophila melanogaster, and that histone deacetylase 6 (HDAC6), a microtubule-associated deacetylase that interacts with polyubiquitinated proteins, is an essential mechanistic link in this compensatory interaction. We found that compensatory autophagy was induced in response to mutations affecting the proteasome and in response to UPS impairment in a fly model of the neurodegenerative disease spinobulbar muscular atrophy. Autophagy compensated for impaired UPS function in an HDAC6-dependent manner. Furthermore, expression of HDAC6 was sufficient to rescue degeneration associated with UPS dysfunction in vivo in an autophagy-dependent manner. This study suggests that impairment of autophagy (for example, associated with ageing or genetic variation) might predispose to neurodegeneration. Morover, these findings suggest that it may be possible to intervene in neurodegeneration by augmenting HDAC6 to enhance autophagy.