Although most NTN children increased the previously qualified as "high" ~ µM affinities of their parents (Figure ), alternative co-evolution criteria may still be explored for further improvements in selected target / parent pairs. For instance, the Nkcc1, Hsp47 and P2x3r, may be some examples requiring improvements. In particular, the lower affinities of Hsp47 and P2x3r may be explained by their incomplete binding cavity. It is possible that targeting their protein surfaces rather than internal cavities, resulted in too weak interactions for co-evolution (Figure ). In this regard, collagen-Hsp47 interactions , may be required to define a complete binding cavity, rather than only a Hsp47 surface. Additional work may help to clarify these possibilities.