Preclinical contraceptive development for men and women

This manuscript endeavors to present research considerations for the preclinical development of non-hormonal contraceptives. Topics include (1) how advances in genomics and bioinformatics impact the identification of novel targets for non-hormonal contraception, (2) the importance of target validation prior to investment in a contraceptive development campaign, (3) considerations on targeting gametogenesis vs gamete maturation/function, (4) how targets from the male reproductive system are expanding women’s options for ‘on demand’ contraception, and (5) some emerging non-hormonal methods that are not based on a specific molecular target. Also presented are ideas for developing a pipeline of non-hypothalamic-pituitary-gonadal-acting contraceptives for men and women while balancing risk and innovation, and our perspective on the pros and cons of industry and academic environments on contraceptive development. Three product development programs are highlighted that are biologically interesting, innovative, and likely to influence the field of contraceptive development in years to come.

Graphene foam as a biocompatible scaffold for culturing human neurons

In this study, we explore the use of electrically active graphene foam as a scaffold for the culture of human-derived neurons. Human embryonic stem cell (hESC)-derived cortical neurons fated as either glutamatergic or GABAergic neuronal phenotypes were cultured on graphene foam. We show that graphene foam is biocompatible for the culture of human neurons, capable of supporting cell viability and differentiation of hESC-derived cortical neurons. Based on the findings, we propose that graphene foam represents a suitable scaffold for engineering neuronal tissue and warrants further investigation as a model for understanding neuronal maturation, function and circuit formation.

Robotic QM/MM-driven maturation of antibody combining sites

In vitro selection of antibodies from large repertoires of immunoglobulin (Ig) combining sites using combinatorial libraries is a powerful tool, with great potential for generating in vivo scavengers for toxins. However, addition of a maturation function is necessary to enable these selected antibodies to more closely mimic the full mammalian immune response. We approached this goal using quantum mechanics/molecular mechanics (QM/MM) calculations to achieve maturation in silico. We preselected A17, an Ig template, from a naïve library for its ability to disarm a toxic pesticide related to organophosphorus nerve agents. Virtual screening of 167,538 robotically generated mutants identified an optimum single point mutation, which experimentally boosted wild-type Ig scavenger performance by 170-fold. We validated the QM/MM predictions via kinetic analysis and crystal structures of mutant apo-A17 and covalently modified Ig, thereby identifying the displacement of one water molecule by an arginine as delivering this catalysis.