alkaloids: the unknown cyclopamine and veratramine; each with different toxicities. Later studies then demonstrated that jervine degraded to cyclopamine upon a Wolff-Kishner reduction, which helped identify the unknown compound. It was also demonstrated that treatment of cyclopamine with a Lewis acid (pH < 2) leads to the production of veratramine. The stomach provides these conditions, and thus only a small amount of cyclopamine passes through the stomach after ingestion. And even though only a small amount of ingested cyclopamine passes the stomach, it remains unaffected afterwards. Veratramine is highly toxic, even if it does not impact development, as it excites the central nervous system and can cause seizures – similarly to serotonin. The mechanism for the production of veratramine focuses on the cleavage of a carbon-oxygen bond, which leads to the formation of a new double bond. From there, this ring is almost aromatic. The driving force to become aromatic then pushes an elimination reaction, creating a third double bond and producing aromaticity, as depicted in the figure below. Mechanism Cyclopamine impacts embryonic development by hindering the sonic hedgehog (Shh) pathway. In healthy development, the Shh gene codes for Shh proteins. These proteins have a high affinity for a surface membrane protein called "Patched". Upon binding, Shh proteins inhibit Patched. With Patch inhibited, another surface membrane protein called "Smoothened" may signal further cascades which impact development. Cyclopamine has a high affinity for Smoothened – and upon binding, inhibits the signal. Even though Shh may inhibit Patched, Smoothened cannot signal in the presence of Cyclopamine and thus the pathway is interrupted. Embryological Cyclopamine causes the most advanced form of holoprosencephaly. Because it blocks Shh signaling, the embryonic brain no longer divides into lobes (becomes alobar). Thus, only one optical track develops, hence the cycloptic (singular) eye. Furthermore, this disease is fatal and presently has no cure. One can imagine one half of the healthy brain not dividing, but instead growing out and resembling the alobar brain. This occurs in cases of cyclopamine poisoning. This malformation is always fatal, and it is worth noting that there are lesser cases of holoprosencephaly that are not always fatal. However, embryonic cyclopamine poisoning causes the most extreme and therefore fatal cases. Medical potential Cyclopamine is currently being investigated as a treatment agent in basal cell carcinoma, medulloblastoma, and rhabdomyosarcoma, tumors that commonly result from excessive SHh activity, glioblastoma, and as a treatment agent for multiple