Design and testing of a humanized porcine donor for xenotransplantation.

Recent human decedent model studies1,2 and compassionate xenograft use3 have explored the promise of porcine organs for human transplantation. To proceed to human studies, a clinically ready porcine donor must be engineered and its xenograft successfully tested in nonhuman primates. Here we describe the design, creation and long-term life-supporting function of kidney grafts from a genetically engineered porcine donor transplanted into a cynomolgus monkey model. The porcine donor was engineered to carry 69 genomic edits, eliminating glycan antigens, overexpressing human transgenes and inactivating porcine endogenous retroviruses. In vitro functional analyses showed that the edited kidney endothelial cells modulated inflammation to an extent that was indistinguishable from that of human endothelial cells, suggesting that these edited cells acquired a high level of human immune compatibility. When transplanted into cynomolgus monkeys, the kidneys with three glycan antigen knockouts alone experienced poor graft survival, whereas those with glycan antigen knockouts and human transgene expression demonstrated significantly longer survival time, suggesting the benefit of human transgene expression in vivo. These results show that preclinical studies of renal xenotransplantation could be successfully conducted in nonhuman primates and bring us closer to clinical trials of genetically engineered porcine renal grafts.

Chemical toxins: a hypothesis to explain the global obesity epidemic.

The number of obese people worldwide has escalated recently, revealing a complex picture of significant variations among nations and different profiles among adults and children, regions, and occupations. The commonly held causes of obesity-overeating and inactivity-do not explain the current obesity epidemic. There is evidence of a general decrease in food consumption by humans and a significant decline in their overall levels of physical activity. There is also more evidence to indicate that the body's natural weight-control mechanisms are not functioning properly in obesity. Because the obesity epidemic occurred relatively quickly, it has been suggested that environmental causes instead of genetic factors maybe largely responsible. What has, up to now, been overlooked is that the earth's environment has changed significantly during the last few decades because of the exponential production and usage of synthetic organic and inorganic chemicals. Many of these chemicals are better known for causing weight loss at high levels of exposure but much lower concentrations of these same chemicals have powerful weight-promoting actions. This property has already been widely exploited commercially to produce growth hormones that fatten livestock and pharmaceuticals that induce weight gain in grossly underweight patients. This paper presents a hypothesis that the current level of human exposure to these chemicals may have damaged many of the body's natural weight-control mechanisms. Furthermore, it is posited here that these effects, together with a wide range of additional, possibly synergistic, factors may play a significant role in the worldwide obesity epidemic.