Embryos derived through sexual intercourse or assisted insemination (Cantineau et al., 2013; Hurd et al., 1993) (left), cultured embryos (center), and SHEEFs (right) start from types of pluripotent cells (zygotes and hPSC; bottom) that have different capacities for development: Embryos formed from zygotes derived sexually can develop into fetuses in utero (vertical arrows, left). Embryos can also be generated from zygotes formed in vitro and these can also result in normal fetuses upon implantation (vertical arrows, center); however, the course of further development in culture is uncertain if implantation does not take place (fading blue arrow, center top), and such experiments are forbidden for ethical reasons (Deglincerti et al., 2016; Shahbazi et al., 2016; Weimar et al., 2013; 14-day rule). Though pluripotent, hPSC exhibit very different courses of development from zygotes that depend on the treatments and culturing conditions and are subject to stochastic effects (short light blue, multi-directioned arrows, right), presumably because they start in a different molecular state from zygotes and do not accurately receive and deliver normal developmental signals. Methods that impose external patterning on hPSC colonies appear able to partly compensate for these deficits and result in SHEEFs that recapitulate more aspects of canonical embryonic development (dark blue A and B vertical arrows, right), as seen in recent experiments by Warmflash et al. (2014) that yielded a version of a Primitive Streak (PS), a developmental feature of early embryogenesis. More sophisticated hPSC cell and tissue engineering methods are expected both to generate SHEEFs that model development more accurately, but also those that develop non-canonically into entities very different from embryos. Meanwhile, a long series of commissions (National Institutes of Health, 1994; Warnock, 1984; National Research Council, 2010) has considered the ethics of experimental research on cultured embryos. These commissions have generally (but non-unanimously) seen the moral status of embryos as increasing (red gradient, top) as they develop the biological substrates of features and capacities taken to be morally significant (moral status signifying features; see text). The 14-day rule arose from basing the research limit for embryo experiments on the first such features to arise in canonical embryological development—the emergence of brain rudiments during neurulation at ~14 days that could, with further development, allow embryos to experience pain. To build in a safety margin the limit was set at the PS, which immediately precedes neurulation in canonical embryogenesis. The fact that the entities produced by Warmflash et al. (2014) have a PS has now led to questions about whether SHEEFs might need to be regulated under the 14-day rule (see text). But while some SHEEFs could model canonical embryo development so accurately that they develop a PS and subsequently neurulate (right, vertical arrow A, which leads into the red zone), this may not be so for others (right, vertical arrow B, which leads into a gray zone with no determined moral status), and it is also possible that sophisticated engineering could produce SHEEFs that bypass the PS entirely but still develop neural substrates (right, vertical arrows C and D). Thus, because a PS may neither be necessary nor predictive of whether a SHEEF could develop a brain rudiment that eventually could experience pain, the 14-day rule may be ineffective for SHEEFs. To overcome these difficulties, we propose that research limits for SHEEFs be based as directly as possible on the biological substrates of moral status signifying features, instead of on canonical embryonic features like PS that do not have intrinsic moral significance. Whereas current guidelines based on canonical embryogenesis assume that a research limit at an early canonical embryonic stage will prevent development of any ensuing morally concerning feature by setting a ‘stop sign’ on a single ‘highway of development’ (red stop sign), our proposed strategy treats morally concerning features as ‘territories in development’ and recommends that research limits be set like ‘perimeter fences’ that prevent entry into them from any direction (red dotted boundary line). Note that the red dotted line in this figure is only meant to depict how a protecting perimeter might be set up, and does not represent our views of where it ought to be set up. The depiction of the female reproductive organs used in this figure was taken from the figure “Human Fertilization” by Ttrue12 under license CC-BY-SA-3.0.