Faces of Neuropsychopharmacology: Percy L. Julian, Ph.D.

sourcePercy Lavon Julian, Ph.D. (1899-1975) was a scientist who rose from humble beginnings, was trained and educated in an adverse cultural era and became a highly accomplished synthetic chemist and entrepreneur (Wikipedia; PubMed; ACS bio). From the American Chemical Society biography:

He was born in Montgomery, Alabama, on April 11, 1899, the son of a railway clerk and the grandson of slaves. From the beginning, he did well in school, but there was no public high school for African-Americans in Montgomery. Julian graduated from an all-black normal school inadequately prepared for college. Even so, in the fall of 1916, at the age of 17, he was accepted as a subfreshman at DePauw University in Greencastle, Indiana. This meant that in addition to his regular college courses he took remedial classes at a nearby high school. He also had to work in order to pay his college expenses. Nevertheless, he excelled. Julian was elected to Phi Beta Kappa and graduated with a B.A. degree in 1920 as valedictorian of his class.

Dr. Julian’s story is a fascinating one and I encourage you to read over the ACS and Wikipedia entries. As you might imagine, he faced discrimination but also managed to find the opportunity for education, including his doctoral studies at the University of Vienna. Dr. Julian turned to private industry for employment after becoming frustrated with the academic pathway. Along the way he founded his own company and nonprofit research institute.
As noted in the Wikipedia entry he laid groundwork critical for many useful products on his way to a total of 138 patents. I was fascinated to read about a fire extinguisher component which he developed just prior to World War II and a lengthy set of contributions to the synthesis of testosterone, progesterone and estrogen.
So why do I choose to highlight an industrial synthetic chemist interested in (cheaper) methods for synthesizing sex hormones and steroids on this blog? It is for one of his earlier and most famous accomplishments, the synthesis of a compound that was pivotal within a highly important and ultimately clinically applied area of neuropharmacology. (This latter being a medium size collection of sciences into which behavioral pharmacology, cognitive pharmacology and several drug abuse sub-disciplines reside.)
Dr. Julian synthesized physostigmine in 1935; previously this compound had to be isolated from botanical material, the Calabar bean. The natural product was known to effectively reduce intraocular pressure in glaucoma thus a method for synthesis was desirable. Apparently this was not a simple task since it took about three years and five papers for Julian and his colleague Josef Pikl to succeed. For those of you that enjoy a good scientific battle you will want to note the ACS bio comment on this:

As it happened in the case of d,l-eserethole, the physicochemical parameters of Robinson’s d,l-eserethole were not in agreement with those of Julian and Pikl. Firm in his conviction that his synthetic strategy was sound, Julian risked his yet-unproven reputation and boldly wrote in the fourth paper in the series that the work of Robinson was in error.

Sounds rockin’!
Physostigmine is an inhibitor of the esterase that breaks down acetylcholine (ACh) which is a reasonably important neurotransmitter. Due to this pharmacological action, administration of this drug tends to enhance and prolong effects which are mediated by ACh. If you do a PubMed search for physostigmine and memory, you will find close to 500 search returns (at this writing). Although the early going featured some mixed results (the oft-cited Deutsch, 1971 is a great place to start) it was at least clear that this compound would manipulate memory ability in animal models. The next half-step in this was an observation by Drachman and Leavitt (1974) that the compound scopolamine, known to block one type of ACh receptor, interferes with memory in humans just as prior studies had shown for animals. Interferes with memory in the non-aged in a manner that was similar to the performance of the aged human subject. Game on!
As you are aware, cognitive failure and particularly memory failure is a distressing symptom of getting older. It is a particularly poignant symptom of neurodegenerative conditions such as Alzheimer’s Disease (AD); in fact one might observe that the loss of self that accompanies severe memory problems is the most feared consequence of Alzheimer’s. From the mid seventies onward, the number of studies using physostigmine to probe memory function and failure in human and nonhuman studies exploded. Leading eventually, as many of you know, to the 1993 US FDA approval of tacrine (another cholinesterase inhibitor) for the treatment of cognitive symptoms of AD. In fact, the current pharmacopoeia for AD is dominated by cholinesterase inhibitors (including brand names Reminyl, Exelon, Aricept and Cognex).
Physostigmine itself didn’t really pan out for AD but I do note that a company named Calabar was trying to bring a physostigmine product to market as recently as 2008.
All in all, not too shabby a result stemming from Dr. Julian’s work in the early 1930s to establish a synthetic method to create a natural product compound. For this alone we should honor him. Throw in the rest of his work on important drug classes such as the sex hormones and corticosteroids and whew, we are not worthy. Thank you Dr. Julian. RIP.
[h/t: I am deeply indebted to commenter Beaker for the pointer to Dr. Julian and to cookingwithsolvents for the additional info.]

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This series of entries (Carl L. Hart, Ph.D.; Chanda K. Akins, Ph.D., Yasmin L. Hurd, Ph.D.) was motivated by DNLee’s call for a new blog Carnival concerned with Diversity in Science. Submit your entries here.