Oftentimes I hear the phrase “technological surprise” used by military planners. It means how can we expect the unexpected? How can we know what might be coming over the horizon that will disrupt our carefully made plans. This is especially true with respect to ‘asymmetric’ threats, such as bioterrorism or biowarfare, where there is the possibility that a key scientific or technology finding might have large consequences.

With this in mind, I decided to do a thought experiment on technological surprise. I went back and thought about all of the (many) times I’ve been surprised about some new finding, and what the upshot of that surprise was. More importantly, I wanted to figure out whether and how I could have anticipated the surprise. There are three examples, one quite timely:

Ribozymes: The discovery of RNA catalysis was rightly worth a Nobel prize. The notion that RNA was not a simple information-carrying macromolecule, but could also act as a catalyst, surprised many scientists. The utility of ribozymes as biotechnology reagents is perhaps not quite as great as was hoped (USB’s early attempt to sell the Group I self-splicing intron as a reagent was largely a flop, and ribozyme companies have by and large not achieved escape velocity), but it nonetheless marked a milestone in how we thought about origins. But it really shouldn’t have been such a surprise. As far back as 1968 Crick and Orgel were musing about the idea that structured RNAs, such as tRNAs and ribosomal RNA, might have more abundant and more ancient functionality than was suspected. And, more importantly, on mechanistic grounds there was nothing keeping RNA from forming a complex structure that might include an active site capable of accelerating reactions. It takes nothing away from the achievements of Cech and Altman to say that ribozymes were foreseeable, however surprising they may have seemed at the time.

RNA editing. I also remember how baroque the appearance of apparently uncoded information in RNAs seemed at the outset. The insertion of multiple U residues, according to no rhyme nor reason based on the accompanying DNA template, was extremely outre. At the time, there were all sorts of wild ideas as to how this might have happened, including some serious suggestions that there must have been an unknown enzyme acting as a Turing machine. On the other hand, my then-advisor, Jack Szostak, just told me. “There’s a template.” I objected, saying they’d looked for a template, and hadn’t found it. Jack would just repeat, “There’s a template.” And, of course, there was. In retrospect, editing was not as mechanistically inevitable as ribozymes. There are still big questions regarding why any organism would want to be so weird-ass when encoding its genome. But the notion that there *had* to be a template, even when there seemingly wasn’t one, is what has remained with me. The mechanistic insight that there were few or no alternatives in technology space to good ol’ template-directed polymerization is part of what makes Jack one of the deeper thinkers of our time. While a Turing machine enzyme would have been a game-changer, an unfound template was by far the more realistic alternative.

Which brings us to: arsenical organisms. There is great fanfare over “A bacterium that can grow by using arsenic instead of phosphate.” The authors suggest that the organism has an arsenate, rather than a phosphate backbone. If this is true, then this is true technological surprise: previously unknown, and potentially an entirely new class of organisms, for good or ill. It’s like the Andromeda Strain dropped into our laps.

But it’s also a technological surprise from the perspective gained by remembering ribozymes or RNA editing: it is mechanistically unheralded. There is no way that an organism can have arsenate in its backbone. To fully appreciate this statement, one can do no better than to refer to my other former advisor, Steve Benner, during the NASA press conference announcing the Science publication: http://www.youtube.com/watch?v=JVSJLUIQrA0. It’s a hoot, and Steve is a consummate showman (as well as an awesome scientist). The bottom line, though, is that arsenate bonds are much, much weaker than phosphate bonds, and therefore the poor arsenical organism is either spending all of its time trying to desperately hold its backbone together (not to mention much of its metabolism) or … it’s not an arsenical organism.

This point is made somewhat finely by the authors, who say that there was background phosphate in the growth media that supported the arsenical organism, and who somehow do not make much of the fact that it is not an obligate arsenophile, growing perfectly well (better, even) on phosphate. It is this latter point that should have raised red flags in abundance. It is hard enough to imagine an arsenical organism. It is virtually impossible, from a mechanistic point of view, to imagine an organism that switches blithely back and forth between arsenate and phosphate in its metabolism. The organism’s enzymes would either have to have substrate specificities that were ‘ambiguous’ to the point of being pathetically slow, or there would have to be some remarkable second genome’s worth of metabolic machinery. And don’t even get me going on the mechanistic nightmare of changing from one backbone / metabolism to the other.

We have visited these issues before, when talking about the unSubtilis and the unColi. The unSubtilis changed its genetic code, a remarkable feat, but not a mechanistically unreasonable one. And in the end it hated tryptophan. It was not ambiguous. The unColi did not really change its genetic code, it became an expert scavenger of tryptophan in a background of fluorotryptophan. And it could grow perfectly well (better, even) on tryptophan. Just like the arsenical organism.

So, I don’t feel like I’m going out on much of a limb when I say that the DNA from this organism will eventually be found to be quite natural. And if I’m wrong, it certainly will not be the first time.

I am going out on more of a limb when I say that NASA should know better. I suspect that NASA has calculated that the repercussions associated with finding biological ‘cold fusion’ will fall on the journal publishing the article, rather than on the agency that trumpeted the article. Perhaps. But do you really think we’re all so short-sighted? That we don’t still remember ALH84001? There used to be a running joke in the community that NASA would find a SETI signal … right before the next Congressional funding cycle. While we all know that science funding is politicized, we usually don’t cross the line from mere begging for funds to outright pandering. It’s a fine line, but I think it’s there for a reason.

- originally posted on Tuesday, December 7th, 2010