  Macromolecules change their shape (conformation) in the process of carrying
out their functions. The imaging by cryo-electron microscopy of rapidly-frozen,
individual copies of macromolecules (single particles) is a powerful and
general approach to understanding the motions and energy landscapes of
macromolecules. Widely-used computational methods already allow the recovery of
a few distinct conformations from heterogeneous single-particle samples, but
the treatment of complex forms of heterogeneity such as the continuum of
possible transitory states and flexible regions remains largely an open
problem. In recent years there has been a surge of new approaches for treating
the more general problem of continuous heterogeneity. This paper surveys the
current state of the art in this area.
