On regulation

Rob Carlson had a piece recently in The Scientist (which has been kind enough to notice this Blog in the past) on the regulation of synthetic biology, in part due to the supposed threat from the DIY Bio community. This seems to be part of a continuing hysterical exchange over a non-issue. While Rob does not actively fear monger for dollars, as do others in the community, he does make statements that unfortunately continue to support a view of synthetic biology as a real-world discipline, as opposed to a collective fantasy.

In particular, I take issue with the notion that “There is every reason to expect that garage innovation will be as important to biological technologies as it was to IT ….” Without revisiting my usual diatribe over whether the term ’synthetic biology’ is meaningless, let’s just look at the details of what is possible. Many of the constructs that folks who claim to be synthetic biologists make contain bacterial or eukaryotic promoters regulated by ‘parts’ such as the Lac and Tet repressors, which have been around for years. Many of these constructs could have as easily been made by PCR as by whole DNA synthesis. Many of the outcomes, whether for sensing or immune modulation, have already been embodied many times over in the literature in circuits known as ‘plasmids.’ Again, this comparison is not to necessarily point out the intellectual paucity of the field as to say: if much of this has been possible for over 30 years, then where exactly is the garage culture that is adding to innovation?

Because I am a verified old person now, I remember my initial excitement with cloning, I remember talking with my peers about all the different things we could make, and I remember that we realized that we could maybe do it on our own … except that it would have been way too hard, compared to the just very hard day-to-day labors of a graduate student. The difference between DIY Bio and Michael Dell putting computers together in his garage is the difference between the availability of the raw materials, not the difference between some supposed lack of standardization then and Biobricks now. There is no ‘Radio Shack’ for DNA parts, and even if there were the infrastructure required to manipulate those parts is non-trivial for all but the richest amateur scientist. And, yes, I not only run my own DNA Fab today, I have in the past made a PCR machine from a hair dryer. I know what’s possible, and I know what’s likely, and I know what works. DIY Bio just plain doesn’t work, and if it did we would have had something worthwhile from the hobbyists long, long before this.

There is going to be no stopping regulation, because there is no stopping ignorance. The community has crafted a fantasy construct, the idea that biology has its own VLSI; it has used this construct to fear monger for dollars; and now it gets to reap what it has sown. Various government agencies believe that synthetic biology exists, and that it has consequences different than biotechnology as a whole, and thus that it needs to be regulated. Forget that every grant proposal we put together to maintain our complicated infrastructure for doing synthetic biology has innumerable layers of regulation attached to it, we somehow need even more scrutiny to keep us from doing … what? Exactly what we said we were going to do in the grant proposal?

But can we at least leave out this part of the conversation, the notion that there could be a black market because folks who hook up platinum electrodes to car batteries and pour agarose gels in Play Doh molds might someday actually create a bacteria that converts glucose to gold?

- originally posted on Sunday, January 23rd, 2011

On artificial proteins

My friend Mike Hecht at Princeton has just published a quite interesting paper in PLoS One (also known as the journal that takes significant findings when no one else will). In this paper (Fisher et al. (2011), 6:e15364) he shows that an expression library of completely random ‘proteins’ of 102 residues in length can suppress a variety of deletion variants that would otherwise inhibit cell growth. Most remarkably, four different deletion variants can be suppressed by the tandem expression of four selected, but otherwise random, proteins.

Now, there are various ways to view these results, as Hecht and colleagues indicate. One possibility is that the selected proteins replace the activities of the deleted proteins (i.e., classic suppression). This is the most interesting and also the most implausible result. It would be truly remarkable if 102 amino acid proteins drawn from a relatively small library of 10^6 different four helix bundle-like proteins had even a fraction of the catalytic activity of biosynthetic enzymes groomed by eons of evolution. My incredulity stems from the difficulties that protein engineers have long had with generating enzymatic activities from scratch (recent successes by Baker aside). In particular, it beggars my imagination to believe that citrate synthase, an enzyme that brings together two substrates and catalyzes the formation of a new carbon-carbon bond, can be replaced by muck of length 102. My beggared imagination is supported somewhat by the fact that the when the small, selected proteins are isolated they do not seem to have the missing enzymatic activity.

So, if it’s not that, then what is it? The manuscript goes to some pains to suggest that it’s also not the activation of an alternative pathway for synthesis, and that it’s not the inadvertent activation of another enzyme that can catalyze the same reaction. Matsumura and his group at Emory carried out a really neat study in which they looked at how some enzymes when expressed at high levels could suppress deletions of other enzymes; that is, they determine whether enzymes could ‘moonlight’ for one another (Patrick et al. (2007), MolBiolEvol 24:2716). They found many examples, but most of these made some sense, in that the enzymes identified had basal activities that were similar to the deleted enzymes. For example, some phosphatases were unsurprisingly found to have loose enough substrate specificities that they could fill in for other phosphatases.

In the end, they don’t know what the mechanism is, which makes many of us (myself included) rather queasy. I continue to believe that enzymes are not easy to make, and yet the results speak for themselves: activity comes from somewhere. There are various other mechanisms that may be plausible, but they sort of boil down to this: complex systems can do complex things. That is, when there are many enzymes around, a new protein may be able to alter another protein’s substrate specificity, induce expression of another enzyme (although, again, not the ones that would have been expected based on what Patrick et al. found), or bring together various other proteins to form new interactions that may fortuitously catalyze new reactions.

So, let’s just go with that: complex systems have many, unanticipated, untapped phenotypic states, and these phenotypic states can be accessed by something as simple as the expression of a random protein. If this is true for something as basic as biosynthetic pathways, might it also be true for other aspects of metabolism, such as pathogenesis or immune escape? Is it possible to change the state of what would otherwise be a non-pathogen to become a pathogen solely by randomly expressing some information? Again, the rational view would be ‘no,’ since presumably many host:pathogen interactions (or pathogen:immune interactions) are predicated on a very delicate and refined dance between pathogen surface markers and host receptors (or immune molecules). And nominally one might think that just throwing in 102 amino acids here or there would not necessarily be the same as crafting a surface glycoprotein that could intimately interact with, say, the transferrin receptor. But really after the Hecht paper, who knows? Maybe there are many otherwise cryptic pathogen markers whose conformations can be altered, whose expression can be induced, or that can be formed into complexes that are much more than the sum of their parts.

In this regard, it’s probably also good to remember that the capacity of the complex cellular genome for expression has also been plumbed, and has again been found to be surprisingly responsive. Several groups have now made ‘artificial transcription factors’ (for example, by randomly fusing zinc finger domains) and then transfecting them into tissue culture cells, just to see what they would do (see, for example, Park et al. (2003), NatureBiotech 21:1208; Blancaford et al. (2003), NatureBiotech 21:269). Perhaps less surprisingly than the Hecht example, these authors found that they could screen for new combinations of DNA-bindiing domains that could turn on and off different genes, and that could elicit novel phenotypes (including fun ones such as drug resistance) in the transfected cells.

So, while we continue to get in a tizzy about the dangers of making long, engineered DNA circuits, here in the background are random screens that are turning up completely unknown and unexpected phenotypes. No one has yet looked for an impact on pathogenesis (so far as I know, but I’m probably just a literature search away from having that ignorance overturned) or immune evasion, but it’s almost certainly possible. Synthetic biology is as nothing to synthetic systems biology, which will rely on bringing out hidden organismal potential, rather than upon jerry-rigging some complex new pathway that may or may not do what it’s designed to do.

- originally posted on Sunday, January 16th, 2011

On communicability

Hey, here’s a riddle: what’s more dangerous than an al Qaeda member with a plane ticket and a shoe bomb? Answer: an al Qaeda member with a plane ticket and no shoe bomb!

OK, perhaps that’s not as funny as I thought. But here’s the point: we are all suicide bombers. Not in terms of our mental potential, but in terms of our awesome potential to spread disease. Each one of us could carry the seeds of pandemic within us. Take the explosion of a single sneeze, and imagine it wafting outwards to a circle of individuals, incubating, and then exploding in another sneeze. Speed up the time lapse and you have a true human bomb, whose radius dwarfs anything from the nuclear era.

Segueing wildly, I note that you can get away with anything in an airport book. I am often caught up by the contrast between being in a relatively sterile, highly controlled environment, and the sheer number of pages within said environment being devoted to serial killers, mass murder, and the like. It’s a bit like having mixology manuals at an AA meeting. Incongruous.

The reason I bring that up is that I assume there will come a point where my thought crimes will be discovered. That is, the fact that I speculate on death and destruction and mayhem will be seen as some sort of indication that I am heavily involved in said acts. To which I reply: airport books.

With that proviso in place, let us veer back into our own lane and talk about a really cool resource, the Influenza Research Database (http://www.fludb.org/brc/home.do?decorator=influenza). This remarkable resource is beautifully organized so that you can find out up-to-date information about numerous parameters about your favorite virus (if your favorite virus happens to be influenza). This actually includes sort of a Google Maps-like representation of where a given virus happens to be a the time. Here, let’s try it:

Now, that’s just some random flu strains from 2007, as opposed to more recent and juicier drug resistant or increased virulence strains. Nonetheless, you get the idea. Or if you don’t, we can create our own airport book:

“Dr. Lecter entered the warehouse, oblivious to the low moans of the animals in the cages on the floor. Only most would not have seen experimental animals, but people, many lying shivering in what little space was available to them. He noted with pleasure that the creature in Cage #31 seemed particularly bright-eyed but mute, the fever from Cage #30 already taking him away. The speed of infection was increasing, as Dr. Lecter had predicted it would. The crossover between the West Virginia and Kentucky variants had occurred. He began spraying down the now useless Cages #14-16 with his own enzymatic brew, Decorpsase, and smiled as the flesh began to melt. Some of the animals looked on in horror; most just stared into an all-too-certain future.”

None of this is to indict the Influenza Research Database, which is a true public health marvel and already contains a number of quite appropriate safeguards. Indeed, even without the organizing glory of this database much of the information is already available via Google, which can now in many cases more quickly and accurately track flu trends than can researchers (what, you don’t believe me? http://www.google.org/flutrends/).

These world trends maps continue to just amaze me. I sometimes think there should be a Google Evil Trends, a map that shows the prevalence of evil in the world at any one place and time. If you followed Evil Trends back into the past there are certain predictions you could make. If we assume that the Web designers had done their job properly, Evil would be black, and certainly there were areas of Poland circa the early 1940s that would have been very black indeed. But as you rotated your globe, you would have come across a region that virtually sucked you into its Stygian darkness: Harbin, China. The home of Unit 731.

This somewhat innocuous-sounding name hid an epicenter of suffering that easily rivaled the better-known Nazi death camps. The site in Japanese-occupied China was home to some of the most horrific human experimentation into biowarfare (amongst other insanities) since the distribution of smallpox-laced blankets to Amerindians. And to bring it all home, there were small, ventilated huts where subjects could be placed side-by-side. It is unclear whether this was to test or evolve communicability, or was merely to give better access to the rats and fleas that carried plague to the hapless victims. The experiments were a roaring success, and led to the development of plague bombs that killed hundreds of thousands.

Pogo and I have previously suggested that we are our own worst enemies. But indeed it is worse than that: our very bodies are our own worst enemies, capable of carrying replicating horrors that will infect our friends and family and children. Perhaps it is an atavistic fear of disease that keeps the rather trivial engineering of communicability from being a reality in our lifetimes. Or perhaps our public health structure will keep disaster from our door. Or maybe we’re just whistling past the graveyard.

- originally posted on Saturday, December 18th, 2010

On technological surprise

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

On dogs

When we recall classic movies of the 1970s I know that everyone immediately thinks of … “The Doberman Gang.” What, you thought I was going to say “Star Wars?” For shame. No, in this gem of American cinematography we have a pack of dogs being trained to rob a bank (and later trained to rip off a corrupt politician in “The Amazing Dobermans” before finally turning away from their lives of crime and working for The Man in “The Daring Dobermans;” Spielberg ain’t the only one who can do sequels poorly). I can barely remember watching this and at the time thinking “What a cool idea!” And I still think it’s a cool idea, although not a particularly practical one. In reality, the dogs sans handler would presumably be confused by the inevitable chaos, start biting people, and get shot.

Now, don’t get me wrong. I like dogs. I *love* dogs. I’m a dog person. But, really, dogs can only go so far. We should not task the criminal utility of dogs too much.

Which is why I am much more worried about dog assassins.

Every now and again there are wonderful, awful ideas (cf. The Grinch) and I open my newspaper in the morning and am happy that said ideas have not made their way into reality yet. For example, the destruction of the American cattle industry by hoof-and-mouth disease. Every day that goes by without that happening is a gift. But a slightly less-awful (although not more wonderful) idea that has again gone whistling past the graveyard is blowing up a public official with a dog.

All the components for dog-as-mobile-bomb are already there, just as all the components for airplane-as-really-big-mobile-bomb were. We have (checklist) … dog. Geared by tens of thousands of years of evolution and selective breeding to be a hunk of intelligent, adaptive, obedient flesh. Our own dog is a bit of an idiot, and did not do all that well when we took a training class with her. However, our instructor, the late Lee Mannix, was a genius with animals. Indeed, I think I learned from Lee that we were much more stupid than she was when it came to training. I also learned from Lee that you can pretty much train a dog to do anything. That said, I don’t want to push it too far, since really all the dog has to be is a semi-intelligent delivery vehicle for the bomb. Next on the list, shock collar. These are pretty nifty little devices, and they actually work. Next, a GPS device. I have fooled around with Geocaching, and it always amazes me that there really is a God in the Sky who tells me where I am and where to go.

Now, take GPS device. Modify with a teeny adapter circuit that essentially provides a shock to different positions on the collar (which will also have to be modified), depending on the relative relation of the dog to its target. This circuit and collar modifications are left as an exercise to the reader, although to prove my own morbid conjectures I did come up with a design that may still be around here somewhere. Spend time training dog to understand that the shock collar tells it where to go. Reward dog for reaching target. Repeat with as many dogs as necessary (for a high value target multiple dogs may be recommended).

Load cute doggie pack up with C4 or other popular explosive. Wire C4 to GPS (again, adapter circuit may be necessary), or else have a cell phone interface if direct observation of target is more reliable. Then: release the hounds, as Mr. Burns likes to say. Many folks smile at cute doggie with cute doggie pack. Even security officials may smile. Preferably, security officials will shoot the doggie. But if there are many doggies, and if security officials are not feeling lucky that day, dog will reach approximate location (commercial GPS is good but not great) and … sadly will not get its reward this time.

The biodefense relevance, for what it’s worth, is this: first, we often neglect the obvious, just as we did on 9/11. Second, animals are biology, too. While we sometimes get all hepped up about molecular circuits, a snoring odor-tracking machine is slumbering at my feet. Third, animals are game-changers, as not only Jared Diamond but several DARPA programs can attest to.

- originally posted on Thursday, November 18th, 2010

On steganography

Isn’t that a cool word? It makes you think of dinosaurs doing dictation, or something. I first came across this word a few years ago when Bancroft and co-workers published a short letter in Nature, “Hiding messages in DNA microdots” (Nature, 399:533 (1999)). But steganography is actually a cryptography method in which you hide a signal amidst a great deal of noise or a great deal of other signal. For example, it is possible to hide messages within digital image files by having some subset of pixels actually encode a letter.

In any event, these authors recognized that steganography would be possible via DNA encoding, as well, and suggested “We have taken the microdot a step further and developed a DNA-based, doubly steganographic technique for sending secret messages. A DNA-encoded message is first camouflaged within the enormous complexity of human genomic DNA and then further concealed by confining this sample to a microdot.” I think there may even be a patent on this technique out there someplace.

But here’s the point: it’s only about ten years later, and this sounds so incredibly dated. It’s like poking Bulgarians with ricin-laced umbrellas, rather than properly exposing them to dioxin or polonium. And why is that? We all know the answer: NextGen sequencing. The enormous complexity of the human genome … is not really so enormous, anymore. Ten years of technology development and, poof, a reasonably clever idea is a joke. Sure, conceal your little oligonucleotide or plasmid or whatever in a bunch of human DNA. Bring it on! We’ll ferret out the unnatural or mutant sequence within, oh, about a day or so.

But let’s consider further. Is it really so silly to consider hiding messages in DNA? Well, actually, yes, given the enormous capabilities for information transfer available with electronics. Of course, there are concomitantly huge capabilities for codebreaking with electronics, and DNA does provide a convenient barrier to immediately tapping a digital format. And it is way more portable than a thumb drive. So, it is conceivable that there may be circumstances where DNA cryptography is a worthy pursuit.

And if so (a really big if) the question would become: how do we further hide the message, in this age of sequence-on-demand? In order to provide future generations (like, what, five years from now) with the ability to look back and chortle at my own foolishness, I suggest the following: alternative base-pairs.

I now must digress just a bit. DNA! I mean, wow! It is an impressive molecule. Not just because of what it does, but because of its incredible uniqueness. You, you there who have taken organic chemistry as an undergraduate, describe for me some other compound that can embed information in a similar way? Mrs. Robinson aside, I scoff at your plastics, which even in block copolymer form are mere random amalgams. I shake my head sadly at your host:guest complexes, which can barely interact specifically by halves, much less by millions or billions. And even the more viable biomolecule contenders, like peptides, are only exceptions that prove the rule. While Reza Ghadiri of Scripps is a stone-cold genius with his replicating leucine zippers, what they really prove to me is how very, very difficult it is to embed information in a replicating system, since the zippers form hypercycles that for the most part like to replicate towards an apotheosis, rather than towards the fixation of a random mutation.

DNA is unique. DNA is da bomb. Almost.

Proving that scientific brilliance can skip a generation, one of my scientific ‘fathers,’ Steve Benner (at the Foundation for Applied Molecular Evolution), and one of my scientific ’sons,’ Ichiro Hirao (at the Yokohama Institute, RIKEN), have designed, synthesized, and used PCR to incorporate non-natural base-pairs into DNA. Steve’s version (Yang et al. (2007), NAR 35:4238) is on the left, while Ichiro’s version (Kimoto et al. (2009), NAR 37:e14) is on the right, below. They have some of the same wonderful properties that DNA itself does: they’re isosteric with the natural pairs, they have bond complementarity and exclusivity, and they can fit into the same backbone that the other bases do. Now, you can sequence all the day long and you won’t find the strands that contain these weirdnesses, unless of course you happen to know in advance that you’re looking for them and have included the appropriate complementary nucleoside triphosphates in your sequencing reactions.

This leads to the question whether the probably limited number of available alternative base-pairs will be co-opted by particular intelligence services, in order to ensure complete secrecy of communications. In some future fantasy world will it be illegal to even describe some of these compounds? Um, no, for the reasons described above (electronics trumps biotechnology in this realm). And even so, we are still exploring whether bond complementarity is all that (go, go Eric Kool!) and whether other backbones are just as good as deoxyribose (a tip of the hat to Albert Eschenmoser). Still, never underestimate the creativity of scientists, and thus a truly facile replicating system that directly interfaces with electronics may yet arise. And if so, cryptography will be only one of its many, many applications.

On history

The weird thing about history is that you don’t appreciate it until it’s over. But of course each of us is living history, every moment. And if we are paying attention, we perhaps see the arc of history, and have some understanding of how we got from there to here, and will get from here to beyond.

This issue has been bugging me recently. I sit in scientific meetings, and I think to myself: “What am I really seeing here? Is this the moment that things change? Is this the time?” Perhaps the very fact that I am thinking these thoughts means that it is not, in fact, the moment. Maybe when history is being made you know it with certainty. In this regard, I look backwards, and try to put myself in the shoes of others:

“[In mid-1933] Edgar Mowrer — who had just won the Pullitzer Price for an anti-Nazi book, Germany Puts the Clock Back — received a politely worded threat. The German government didn’t like his opinions and wanted him to resign from his post as president of the Foreign Press Association …. Edgar was informed that the German government could no longer guarantee his safety. He left for France …. ‘Nowhere have I had such lovely friends as in Germany,’ [his wife] wrote afterward. ‘Looking back on it all is like seeing someone you love go mad — and do horrible things.’” (Nicholson Baker, Human Smoke, pp. 39-40).

“When Jewish scientists were dismissed en masse from their jobs in the spring of 1933, following the rise of Hitler, their jobs were promptly taken by their non-Jewish junior colleagues. This so puzzled British scientist George Barger … that he wrote to Karl Freudenberg, a well-known non-Jewish professor of organic chemistry at Heidelberg …. Freudenberg replied as follows: ‘There are orders which you simply have to comply with. It is my firm conviction that a cure of the body of the German people was necessary, something which probably only very few will deny. The way it has been carried out cannot be subject to lengthy considerations in this country, simply because there are orders, and it does not matter at all, what the viewpoint of the individual is.’” (John Cornwell, Hitler’s Scientists, p. 127)

It is an Internet trope that once the Nazis have been invoked all further discussion is moot. And so it is with little credibility that I suggest that wondering about the anti-evolution sentiments that sometimes flare up in my adopted state, or that seeing the anti-immigrant policies that are rife around the country, or looking on as the Chinese claim the human metagenome are somehow echoes of what must have been occurring in 1933. But I continue to wonder what my counterparts, sitting bored in the last row of some scientific meeting in 1933, were thinking. And whether they knew what was really happening, what was about to come.

Or whether everyone in any given present is of necessity myopic (OK, Leo Szilard was not myopic; he was one smart mofo).

Still, whether or not I can see clearly, I think I can still find my way by sound. And somewhere between the reverberations of the Tea Party and the drumbeat of China’s industrial muscle I think I hear a far, keening note that bodes ill for us all. That dumbing down America while the rest of the world absorbs and acts on our hard-won knowledge is not at all a good thing. And most importantly that American industry, which last century could be counted on to come to the rescue of a stalled economy and which drove major war efforts is now quietly slipping out the back door and setting up international offices. What really is the point of a nation state when all that nation state has left is power projection?

Such questions can drive you to distraction. And thus I think that the only rational choice is the arrogant notion that you can, indeed have an obligation to, change history. That you make the best call you can, and move forward by doing the right thing.

- originally posted on Monday, November 8th, 2010

On molecular computation

Like many folks, I was fascinated with Len Adleman’s adaptation of DNA to serve as a computational entity (Adleman (1994), Science 261:1021). This was just really cool, especially in that it both encoded a problem in a nucleic acid, and then asked the nucleic acid to solve that problem based on what I like to think of as ‘hybridization logic.’ This idea quickly permeated the community, leading some to speculate that massively parallel DNA computers would be able to crack the data encryption standard that keeps our money (amongst other things) safe (Adleman et al. (1999), J Comp Biol 6:53). DNA computers (actually, RNA, to be completely wonkish) even surged to the forefront of cultural memes by being included in the Intrepid Class Starship Voyager.

So, why don’t we all have DNA computers now? There are many answers to this question, but they all sort of boil down to this: DNA computers suck. They are error prone, they don’t scale, and they are extremely poor competitors to silicon-based devices. There are of course those who would argue (correctly) that *we* are DNA-based computers, and we don’t suck. We are in fact supremely good at signal processing and pattern recognition, things that silicon computers are still catching up on. However, I would in turn argue that these features have everything to do with architecture, and not much to do with DNA. We don’t yet really know how to properly emulate a biological computer. But that said, the converse is not only true, but inherently true: I do not believe biology will ever adequately emulate silicon-based devices. Neural interconnects are not nearly fast enough, and whatever else our architectures do, they suck at calculations. Even if you take one of the savants that Oliver Sacks has popularized, their pure number-crunching capacities are much less (and much slower) than your average hand calculator. So, outside of Dune we shall not have mentats, how sad. There goes my idea for a eugenics program for savants. Probably just as well.

Ahem.

I always like to think of DNA computation as a good example of a failed technology arc. Initial publication, extraordinary excitement, multiple imitators, but little followup. Most of the publications in high impact journals, without much fleshing out in the second tier. A field driven by journal editors rather than by scientific utility.

And there DNA computation would have remained, except for the fact that it was intellectually … interesting. And scientists have a way of taking even the most arcane ideas, and playing with them until they pan out, even if it’s not in the way that was originally expected. From my vantage, what happened was that folks began to realize that DNA was never going to displace or even challenge silicon at what silicon was good at, and therefore it might be useful to consider how DNA computation might be useful to living systems themselves. The notion of “DNA on DNA” computation arose. And as that notion was fleshed out, information encoding became a lesser issue, and the actual silicomimetic features of the molecules themselves (to use a phrase from Milan Stojanovic of Columbia) came to the fore.

My friend Erik Winfree at Caltech would likely disagree with this interpretation, and he should be listened to: he was there for the inauguration of the field, and is at the forefront of what I like to think of as its Renaissance. He sees an unbroken intellectual lineage where I see a discontinuity. It is Erik who has more recently invented a form of DNA computation based on strand displacement (Seelig et al. (2006), Science 314:1552; Zhang et al. (2007), Science 318:1121). This model has proven to be not only intellectually compelling, but versatile. Layers upon layers of DNA circuitry can be successfully stacked. Real-world applications can be envisioned. And many lesser publications have quickly followed on the heels of the seminal ones. Moreover, the recognition that nucleic acid structural reorganization can be used as a ‘matter computer’ (in the words of Zack Simpson) has sparked new instantiations of Erik’s breakthrough, including a quite novel DNA self-assembly scheme pioneered by Niles Pierce and Peng Yin, also of Caltech (Yin et al. (2008), Nature 451:318; although Peng has now moved to Harvard).

Because of these advances, which I certainly did not anticipate but now celebrate, it is in fact possible to imagine operating systems that are symbolically encoded yet laid out in DNA. Which means that a rational biology based on programming may indeed be within our reach. It will require massive recoding, since evolution engineers by chance rather than design, but it is nonetheless for the first time more than just a science fiction story.

- originally posted on Saturday, November 6th, 2010

On influenza

Not much of scientific worth today. Rather, just a perspective. I guess if I have a hobby, it’s reading history. I hated history when I took it in school, because it just seemed to be a bland regurgitation of dates (it is unclear why I didn’t hate science, which was largely a bland regurgitation of facts). But I love reading it now, especially historical fiction, which provides a narrative to the reality (I highly recommend “Gates of Fire”).

Every now and again I come across a history book that touches on my professional life. “Rats, Lice, and History” is one such book, and again is highly recommended. But for sheer impact there is almost nothing to compare to Richard Collier’s “The Plague of the Spanish Lady.” Despite the vaguely racist-sounding title, this book is a remarkable compilation of historical (and for the most part, personal) accounts of the 1918 influenza pandemic. This killer flu took out a huge number of folks worldwide, and depending on the guesstimator (it’s my word, I’ll spell it how I want) may have felled up to 5% of the world’s population. A malady seemingly on the order of the Black Death or the Plague of Justinian, given that it occurred less than 100 years ago in a world that had some knowledge of advanced practices in public health and medicine.

I bring up this book because there are certain passages that stuck in my brain, and continue to resonate. If I have an interest in biodefense, it is in large measure because of this book. I will share one such passage with you, and you can see if you are now similarly inclined (pp. 37-38):

“On one factor, at least, all doctors agreed: only in cholera did the collapse come so suddenly that most victims could fix the precise moment when they fell … most often this killer-virus struck like a lightning-bolt ….

“By the Galeria Cruzeiro, in the heart of Rio de Janeiro, a man accosted Ciro Vieira Da Cunha, a young medical student: ‘Excuse me, does the tram for Praia Vermelha stop here?’ ‘Yes, it does.’ ‘I am much obliged to you.’ With this banal exchange, the man fell dead ….

“Off-duty in Cape Town, Driver Charles Lewis of the Transport Corps boarded a train for his parents’ home in Sea Point, three miles distant — but barely had the conductor signaled the start than the man collapsed on the platform, dead. It was Lewis himself who acted as starter — but within minutes a passenger had fallen dead, then another. Five times the tram was stopped to place the still-warm bodies on the pavement, for collection by municipal carts — but three-quarters of the way to Sea Point the driver, too, slumped forward and died. Absurdly glad to still be alive, Lewis walked home.”

People going about their everyday lives all across the world, perhaps with the sniffles. And then they die. That was the 1918 pandemic.

The seemingly unique nature of this flu relative to others that have arisen (and may yet arise) does raise a number of interesting questions. First, what would happen if this virus was loosed upon modern society? Would the extraordinary interconnectedness of our planet mean that the death toll and dislocation would be multiplied many times over? Or does the fact that almost every corner of the planet now has a public health infrastructure of some sort, however primitive, mean that the virus would be stopped in its tracks, as SARS was (this is making the leap that we didn’t just get lucky with SARS, which is my own estimation)? Would the spread of immunization against other influenza viruses provide enough protection against this killer that it would lack the human hosts necessary for spread and evolution?

And is the 1918 influenza actually that unique? Is it just a rare combination of alleles that remains a potentially deadly threat? If so, then there may be some justification to those who have suggested that the release of the sequence and the resynthesis of the virus were big mistakes. Certainly there is now ongoing research into the nature of the 1918 influenza that can be seen either as a means of combating deadly influenza viruses when they arise, or as a slow roll towards disaster. I tend towards the former viewpoint, but respect the latter.

But even as I respect those who fear, I do argue against them. It is a hard argument to win, in part because fear does not usually respect rationality, and in part because fear stems from unknowns, which cannot be argued away easily. Yes, the boogey man or boogey terrorist organization or boogey state can in fact make 1918 influenza with relative ease. As previously stated, any small virus can be readily synthesized, and the reverse genetics of influenza are well-known. So, now what? Do we lock away all the knowledge and technology that just might lead to the horror aptly stated within the old nursery rhyme: “they all fall down”? If so, then there are alot of barn doors that need to be closed, and alot of PhDs that need to be put behind fences of one sort or another. It would be rather like saying that transistors should be export-controlled because computer viruses might one day arise.

The alternative view is that the only way to fight bad is with good, and to assume that good is either more powerful or more populous than bad. In the words of the great sage Walt Kelly and his mouthpiece Pogo Opossum: “Good is better than evil because it’s nicer.” I tend to believe that educating an army of white hats is the best way to combat black hats. The black hats will always be there, and there will always be some very clever ones (see also Kaczynski, Ted). Our only hope is … hope. That we are better. And to that end, we should exercise hope, the hope of knowledge, the hope of research, the hope of technology for a better future. I could have stated this much better, but I think I stated it just right.

- originally posted on Sunday, October 31st, 2010

On Texas

Texas is my adopted state, I’m originally from the Midwest. Like many transplants, I find the place to be freaky. On the one hand, there is a certain frontier mentality that is refreshing. On the other, there is a certain retrograde mindset that is terrifying. Let’s start with attitudes towards the government. Our gubnor is in a constant pissing match with the Feds over, well, not much except his own political future. But this message resonates with Texans, who like to envisage themselves as embattled and downtrodden by the heavy-heeled boot of authority.

Well, yeah. Any modern technological society has a large component of top-down control. The great thing about the US is that we get to participate in that top-down control to a large extent. As someone in the military once put it to me, we get to have a revolution every four years.

What I find disconcerting is the logical disconnect over the presumed Utopia that would arise if only we could get government off our backs. We’d, what, put up our own stop signs? Maybe a toll booth in my driveway? Have some ‘well-regulated militias’ rounding up the illegal immigrant backbone of the Texas economy? I think it’s this latter concept that I find most amusing, the notion that I have individual responsibilities to personal safety and freedom that supercede an elected government. Yes, that’s right, the centrality of the Second Amendment as a means of ’spilling the blood of tyrants.’

Now, I’m actually a big fan of the Second, and in general do not like abrogating it. However, my mind can be changed by circumstance. I’ve had lots of arguments with my graduate student friend John Woods over whether there should be concealed carry on campus. I generally said “Who cares, sure,” right up until yet another disgruntled Texan decided to carry an AK47 into the University library. I wasn’t here for that fiasco, but what impressed me was the ruthless efficiency of the jack-booted thugs, er, I mean the police. Whoa. These folks were totally on top of things. And so I can only imagine what would have been the case had some undergraduate yahoos decided to brandish their own weaponry. It would have been an unregulated bloodbath, with the undergraduates getting the worst of it.

And this, then, is the point: the ability of the average American to defend themselves against the government, or even against fairly well-organized criminal gangs, evaporated around, I dunno, 1920 or so. Exactly what is it that I’m supposed to do against a blood-filled tyrant who has an armored personnel carrier?

The Second Amendment priesthood usually does not make the appropriate logical leap: I should be able to have my own TOW, gordamit. But you hardly ever see that argument for public consumption. However, the real savants in this realm, such as the not-very-well-regulated militia known as the Republic of Texas recognized that asymmetric warfare is the only way to go. These stalwarts attempted to develop their own biological and chemical weapons base. Like any insurgent group, they recognized that the government was not going to be confronted with pea shooters. Similarly, in 1998 the North American Militia in Michigan decided to develop home brews for the production of ricin. Now, leaving aside the heady problems of dispersal, this is actually not that hard a thing to do. Heck, we’ve produced ricin in quantity over the years for studies ranging from crystallography to antidote development, and the protocols are probably still kicking around in the background somewhere.

But having the means does not equate to the insanity required for use. Beyond the massive regulatory apparatus that I must pay obeisance to, the usual factors (mortgage, family, age, and sloth) make any pretense of being a revolutionary only a fleeting thought. Not to mention that I actually think we have the greatest political system ever invented.

But perhaps it’s only the threat that counts. After all, in standoffs between those with guns and those with badges it’s usually the media component that is asymmetric, not the firearms. And so perhaps I serve the purpose of keeping the blood-filled tyrant at bay by merely having access to the asymmetric weapon of an extensive knowledge of chemistry and biology. In this regard, and as a paean to my adopted state, perhaps I should say “When biological weapons are criminalized, only criminals will have biological weapons.” Wait, that sounds far too rational.

I know: “You will pry my DNA synthesizer from my cold, dead hands.”

- originally posted on Monday, October 25th, 2010