Although much progress is being made in understanding the molecular pathways in the placenta involved in the pathophysiology of pregnancy related disorders, a significant gap exists in utilizing this information for developing new drug therapies to improve pregnancy outcome. On March 5–6, 2015, the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health sponsored a two day workshop titled Placental Origins of Adverse Pregnancy Outcomes: Potential Molecular Targets to begin to address this gap. Particular emphasis was given in the identification of important molecular pathways that could serve as drug targets and the advantages and disadvantages of targeting these particular pathways. This article is a summary of the proceedings of this workshop. A broad number of topics were covered ranging from basic placental biology to clinical trials. This included research in the basic biology of placentation, such as trophoblast migration and spiral artery remodeling, and trophoblast sensing and response to infectious and non-infectious agents. Research findings in these areas will be critical for formulating developing future treatments and developing therapies for the prevention of a number of pregnancy disorders of placental origin including preeclampsia, fetal growth restriction, and uterine inflammation. Research was also presented summarizing ongoing clinical efforts in the U.S. and in Europe testing novel interventions for preeclampsia and fetal growth restriction, including agents such as oral arginine supplementation, sildenafil, pravastatin, gene therapy using virally-delivered vascular endothelial growth factor, and oxygen supplementation therapy. Strategies were also proposed to improve fetal growth by enhancing nutrient transport to the fetus by modulating their placental transporters, as well as targeting placental mitochondrial dysfunction and oxidative stress to improve placental health. The roles of microRNAs and placental-derived exosomes, as well as messenger RNAs, were also discussed in the context of their use for diagnostics and as drug targets. The workshop discussed the aspect of safety and pharmacokinetic profiles of potential existing and new therapeutics that will need to be determined especially in the context of the unique pharmacokinetic properties of pregnancy, as well as the hurdles and pitfalls of translating research findings into practice. The workshop also discussed novel methods of drug delivery and targeting during pregnancy using macromolecular carriers, such as nanoparticles and biopolymers, to minimize placental drug transfer and hence fetal drug exposure. In closing, a major theme that developed from the workshop was that the scientific community needs to change their thinking of the pregnant women and her fetus as a vulnerable patient population for which drug development should be avoided, but rather thought of as a deprived population in need of more effective therapeutic interventions.

Adaptation to the environment is one of the fundamental regulatory processes in biology and is found among both simple and complex organisms. In a changing environment, simple organisms enhance species survival by high rates of spontaneous mutation achieved by several means: short maturation rates, rapid rates of reproduction, recombination through sexual reproduction, and large numbers of offspring. Then, by a process of natural selection, organisms that are adapted to their environment will survive and multiply. The process of natural selection also affects complex multicellular organisms and promotes adaptive changes. However, this simple strategy for survival becomes less effective in multicellular organisms as the ecological niche becomes more complex and the rates of maturation and fertility decrease. As a result, changes in the environment outpace the rate of genetic evolutionary change, which is limited by generation time. How do multicellular organisms produce adaptive change without genetic mutation?One solution to this problem is the development of complex physiological and behavioral systems coordinated by a CNS. The nervous system permits rapid adaptation to changing environmental conditions without genetic mutation (Kandel, 1984) by coordinating inputs from the internal and external environment via receptors and directing a complicated physiological response through various effector systems to maintain homeostasis. In many instances, homeostasis is maintained by reflexes and fixed action patterns in response to a stimulus. A problem arises when a stimulus or event in the environment does not determinately predict a condition or appropriate response to that condition.To cope with environmental complexity and ambiguity, an organism requires mechanisms that allow experience to affect relatively long-lasting changes in behavior. With a nervous system, the organism can accomplish this through a mechanism that has been called learning (Scott, 1965;Hilgard and Bower, 1975). According to the cellular connectionist hypothesis of Tanzi (1894) and Ramon y Cajal (1894), behavior modification is achieved by the strengthening of preexisting connections and by recombining potential combinations of dormant pathways between neural pathways that mediate innate response laid down during development or by the growth of new connections. Thus, recombination of connections between structural pathways increases the information storage capacity of the nervous system. So, how does the nervous system generate the diversity of cell types and connections and form long-term changes in synaptic connections as a result of experience (memory) with only 20,000 -30,000 genes in the vertebrate genome? Although somatic mutation in neuronal precursors through retrotransposon hopping has been proposed (Muotri et al., 2005) to generate diversity in the nervous system, as it does in the immune system, it is more likely that permanent changes in gene expression patterns are achieved through permanent changes in chromatin remodeling without...

Much biomedical research continues to focus on a small proportion of the human genome that has already been studied intensively. The Illuminating the Druggable Genome programme, initiated as a pilot project by the US National Institutes of Health Common Fund in 2014, is now being implemented to accelerate the investigation of subsets of understudied proteins that have potential therapeutic relevance.