It might be expected that substances so refractory to lysosomal degradation
would also be very long-lived in the soil after death, and would thus be
detectable in locations such as graveyards. This might not be so, however,
if the soil harbours organisms with hydrolytic capabilities exceeding our
own. Such organisms are indeed present. Within the soil bacteria, the
Nocardioforms (a diverse group of Gram-positive bacteria) play a central
role in the recycling of highly recalcitrant, water-immiscible or poorly
soluble compounds such as aromatic hydrocarbons, halogenated hydrocarbons,
oils, fuels, solvents -- even explosives. If such organisms can break down
highly cross-linked material that is resistant to the human hydrolytic
machinery, it is a conceptually straightforward (though, of course,
technically very challenging) matter to isolate the enzymes responsible and
incorporate them transgenically into affected cells. There should be
little danger to lysosomal integrity, since that is mainly ensured by the
extreme glycosylation of lysosomal membrane proteins and the presence of
highly specialised lipids in the inner leaflet of the lysosomal membrane,
whereas the target material is mainly derived from heterogeneous lipids.
(An even safer mode of delivery may be via engineering of Leishmania, which
naturally targets and survives within macrophage lysosomes.) Preliminary
experiments, whose results will be presented, indicate that such bacteria
can indeed degrade such substances, since they grow on them in the absence
of any other nutrient.
Key words:
lipofuscin; foam cells; neurodegeneration; Nocardioforms; gene therapy
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