On graduate students

As any faculty member knows, graduate students are our future. Or, more precisely, graduate students are the serf-like remnants of an ancient, hierarchical Germanic university culture that we continue to pretend drives innovation in the world. This pretense has some basis in reality, since graduate students are often very smart, very motivated, and very productive. Which ultimately is good for the faculty members who feed, vampire-like, off their productivity.

Graduate students are also great because they haven’t yet learned that they can’t really do anything important. This is a lesson most academics inculcate at some point in their careers (although of course the best ones do not). So, it’s fun when a graduate student comes to me with a Great Idea, shiny and new and ready to be shot down.

Most recently, a student in the extraordinary Marcotte lab, Jeremy O’Connell, came to me with an idea for how to use yeast to synthesize heroin. This warmed the cockles of my heart, because it’s about the fifth time I’ve heard this idea, dating back to when I also thought that I had uniquely thought of it, way back in, well, graduate school. Anyone who’s ever read anything about the wonders of secondary metabolism recognizes that organisms rule in terms of controlling regiospecific reactivity and carbon flux, and in turn find it surprising that the organic artistes make any money at all. However, in the absence of a centuries long breeding program to make addictive drugs something like 50% by weight of a leaf, it is actually hard to convince organisms to make complex metabolites, no matter what pathways may be known.

Nonetheless, metabolic engineering is big business, or at least is becoming big business, and the tools for convincing organisms to do things that they would not otherwise do are many and varied. Most recently, Hawkins and Smolke (Nat Chem Biol 4:564) had the clever idea that a commercially available compound, norlaudanosoline, looked something like a natural intermediate in relevant alkaloid biosynthetic pathways, and decided to try to convince yeast to use this compound for the production of a key intermediate, reticuline. The plant enzymes they used had enough play to allow this, and the yields were not bad (although starting a bit farther back, with dopamine, did not work so well). Even weirder and more interesting, a human enzyme could be used for a key transformation to salutaridine, which is getting reasonably close to morphine (and thus reasonably close to heroin; see also “On ingenuity”).

Now, Jeremy discounted the several, several steps from salutaridine to morphine, but let’s let that slide for the moment. What he did notice is that science marches on, and that researchers had identified a couple of key demethylases necessary to get from the intermediate thebaine to morphine (Hagel and Facchini, Nat Chem Biol, 6:273). That is rather interesting, given the aforementioned Hawkins and Smolke paper. It suggests that there may now just be a smallish gap left to bridge norlaudanosoline to morphine (that gap would be from salutaridine to thebaine, a measly two steps), and again from there to cocaine.

And keeping in mind that semi-synthesis involving both biology and chemistry is always a possibility, there may be pathways yet to be imagined that meld the street chemistries and chemists that were discussed in “On ingenuity” with the synthetic biology discussed herein. I again find this to be an especially intriguing combination, in that it goads the great minds with the invisible hand (or, as Jay Keasling wrote in a piece accompanying the Hawkins and Smolke work, “the worldwide sales of some of the most widely used alkaloids, including caffeine, nicotine, cocaine, and heroin, exceeded $US 4 billion in 2002″).

So, Jeremy, the ball is in your court. Finish the synthesis, and shake, shake, shake that goading invisible hand (or, as he put it in an E-mail to me: “At this point its probably just a matter of time.”). Now, I’m not really suggesting this, as I am not suicidally inclined to undercut the profit motives of large narcoterrorism empires. But Jeremy could have perhaps put it differently: “At this point its probably just a matter of who.” Not us (no, really), but someone. This of course ignores the many, many difficulties that yeast in a vat face relative to their sun-baked, highly bred green competitors (and don’t even get me going on price points), but where there’s a graduate student, there’s a way.


- originally posted on Sunday, October 17th, 2010