On fear

I am almost (but not quite) of the generation that you can ask the question of: “Where were you when JFK died?” For those of you who do not know who JFK was … well, that’s just sad. Anyway, I do remember where I was when JFK died.

The modern version of this question may be “Where were you when 9/11 happened?” I was in my lab, doing my usual work, and got to listen on the radio to much of the horror with my students. It was so surreal, as it must have been for many of you.

And then there were the “Amerithrax” attacks, on the tail of the general horror. I was cleaning up piles here at home, and I chanced across something the University put out around that time “Commonly Asked Questions About Bioterrorism.” It is instructive. “Individuals should not store antibiotics at home.” Well, that’s pretty much true. But pointless. If you think you’re going to die, you are not going to trust the government to save your life. Heck, we don’t even trust the government to provide us with health care. “Can we obtain anthrax and smallpox vaccines?” This was interesting because … smallpox? What? I don’t recall there being a big smallpox scare at the time. I guess the University Health Services just picked a disease out of the hat, to show that we were on top of things? “What should I do with suspicious mail?” Oh my, the suspicious mail. I had folks cold-calling me to ask me to test their mail for anthrax. I did what I usually do in such situations: set a price point so high that they are discouraged, unless they’re super-rich. Knowing super-rich, super-stitious folks is not necessarily a bad thing. Anyway, one of the best recommendations the UHS gave us was: “As soon as practical, shower with soap and water.” I love this because at first glance it seems stupid, but it’s perhaps the best public health advice of all time. Seriously, I think we’ve avoided so many plagues just because we’re cleaner now.

OK, I know I’m babbling a bit here, which is what most reminescences are. “People wore onions on their belts, which was the style in those days,” as I believe Abe Simpson likes to say.

But I do have a point in here somewhere. And that point is this: we were taken down as much by fear as by anything else. Several folks died, which is tragic and horrible. But many more folks die in car crashes on most days, and we don’t run screaming from our vehicles. Yet we did begin to microwave our mail, refuse to go outside, and various other odd behaviors. They went away, it’s true. But we were taken down by fear.

Now, suppose we ever had a real catastrophe, one that actually resulted in many thousands of deaths or illnesses. We would be beyond paralyzed. The psychic aftershock would put us down for the count.

And it’s because we’re primed to be afraid. We are conditioned to not understand and to therefore run around like chickens with our heads cut off. To my great shame, I canceled a trip post 9/11. But with respect to bioterrorism, it’s even worse. Most people don’t know what smallpox is anymore, much less why we should or shouldn’t worry about it. Heck, many people don’t even believe in the utility of vaccines anymore.

And this is where my beef with the government really starts. It’s not that we don’t have a good vaccine program, or that we don’t have good public health programs or emergency response capabilities or even some sort of plans on how to quarantine. I actually think that in terms of command and control we’re doing a pretty good job.

But the one incredibly cost-effective thing we could do, educate the public, is nowhere. In various forums I have advocated just having the Surgeon General come on the TV once a month for 15 minutes (or do a YouTube video, whatever) and explain disease. Explain how we responded to the last incursion of smallpox in the US, in the 1950s. Virtually all of NYC was vaccinated within a short period of time. Or how our ancestors more or less knew how to deal with yellow fever. It made many sick, and some died, but we got through it. We need to demystify disease and how disease is spread and how disease is handled. We need to make responding to bioterrorism as commonplace as getting screened in the airport.

Until that time we’re primed to be taken down as much by fear as by anything else. It often amazes me that our adversaries don’t see how much cost-effective damage can be done by a well-placed letter to the New York Times.

- originally posted on Saturday, August 21st, 2010

On invisibility (paradoxically, with pictures)

So, you’ve heard me yammer about augmentation, chemical, biological, human. There’s nothing particularly special about this word. Other folks talk about engineering. Same difference. I guess I just like the word because engineering always seems to inherently presume that you have a precise goal in mind, or a set of known tools that you’re using. That could just be my bias. But to me, augmentation is … more open-ended.

Previously I talked about the amazing unSubtilis and the slightly less amazing unColi. Organisms that can incorporate fluorotryptophan throughout their proteomes. An academic feat, right? A mere fillip on the flank of science (yeah, I got that word from my man Rex Stout). Ah, but what else might it mean?

Seguing wildly, there is the classic H.G. Wells tale about the Invisible Man, and the slightly less classic SyFy series.

And then there are the un-organisms, mentioned above. How do we see organisms? Well, beyond the usual microscopy methods, there is the fact that many organisms have a different fluorescence profile than, say, your average speck of dust. And this different fluorescence profile is due in part to the native fluorescence of the aminio acid tryptophan, which is contained in many proteins throughout the cell.

But here’s the deal. In addition to its amusement value, fluorotrpytophan has a different fluorescence profile than normal tryptophan.

That’s right, fluorotryptophan is as invisible in its own way as the hapless Dr. Griffin.

Well, so what? For time immemorial invisibility has been prized by as a tactical or strategic advantage. Usually we call it camouflage or secrecy or whatever, but if your adversary don’t be knowing you’re there, then the advantage be yours. Or the more elegant Sun Tzu suggests: “Ethereal, a master leaves no trace to be seen, mysterious under Heaven, he leaves no sound to be heard. By these two, a master seals his foe’s fate.”

Which brings us to the impact of invisibility on the modern battlefield. One strongly suspects that the impact of bending light by the trick of CCD detection and projection has not been lost on the military. But what of fluorescently invisible bacteria? Could they be a threat? Oh yes. Here is one way we detect non-fluorescently invisible bacteria that might be part and parcel of a biological attack, the BIDS.

So, here’s the deal. Could someone make an unAnthrax? And would the BIDS detect it? I don’t know. But I hope someone is thinking about this, and not just about the possibility of some super duper engineered genome (again the subject of an earlier rant). Because unlike the super duper engineered genome, the invisible bacteria is something that is well within current technological capabilities. And also unlike the super duper engineered genome, the invisible bacteria is not something we might normally think about, like flying airplanes into buildings (again the subject of an earlier rant).

- originally posted on Friday, July 30th, 2010

On human augmentation

Today I’m at the NSSEFF meeting in Virginia. I was lucky enough to get one of these DoD Fellowships, and I thought I should show up and thank folks in person. Actually, this is a prelude of what I’ll have to be doing in future years, reporting on my own efforts to make NeoLife, programmable organisms with novel chemistries.

What catches the eye, though, is the skew of physical versus biological (or even chemical) scientists. It’s hard to touch on the military or intelligence communities at any level and not realize this: that the physical sciences and mathematics are far more important to our preparedness and response than is biology. This is as it should be: the advantages we reap from supercomputers and signal processing and new materials are huge. Even outside the military the skew is evident in our fascination with cell phones and cyberspace and robotics, which touch on biology but are very much apart from it.

Need it have been this way? I recently read a fun book, Leviathan, which is more or less an adolescent’s science fiction book (and my boys have found it a good read, as well). It is an ‘alternative history’ of World War I, to a first approximation, played out against a different technological backdrop in which the German equivalents have advanced robotics (clankers) and the ‘Darwinists’ of England have engineered every aspect of biology, creating great beasts of war and commerce.

Now, while it’s true that in our modern age we do not have the promised Gundam of yore, it is nonetheless clear which of these two extreme technological paths we are closer to. A few years ago we could see the fictional Ripley suit up in an exosuit loader to fight an Alien queen, and today we can look at something remarkably similar coming out of DARPA’s exoskeleton program. Indeed, focusing only on the last several hundred years we seem to have been better at imagining and engineering great machines rather than great beings (the prescient works of Jules Verne leap to mind).

It is possible that this skew is inherent in the nature of technology. The physical world has always been useful as a human augment, on a human timescale. It is easier to pick up a stick than to evolve claws. And precisely because evolution has occurred and occurs, unabated, to give us what advantages it can, the physical world has been and to some extent remains the high frontier, from our ancestors onward.

But it is also possible that other aspects of the human condition have argued against augmentation of the species. We were not shy to mold the animal form. Our amazing achievements in animal and plant husbandry have been almost the definition of civilization for thousands of years. The breeding of horses and dogs and plants was a science even prior to providing essential clues to Darwin, Mendel, and other researchers. And despite some resistance, genetically engineered foods have changed the world.

So, why haven’t we embraced eugenics? Why is human cloning banned by almost every government on the planet? And why do militarily expedient programs in human performance enhancement still focus almost exclusively on drugs rather than genetic engineering?

Oh come on. You know the answer.

- originally posted on Friday, July 30th, 2010

On red teaming

I have at various times and in various places participated in ‘red team’ exercises, where my job was to think about how to do damage to the United States of America. As I may have alluded to elsewhere, it is a surprisingly easy thing to do. The one unfortunate thing about living in a largely free society is that it is a very, very vulnerable society. It’s a bit weird and wonderful: we trust each other. And because we trust each other, things work. I stop for the Stop signs, you stop for the Stop signs. Not every country is like this; in fact I’m not sure there are many other countries like this. Kleptocracies abound, and it is really, really hard to pull back from a kleptocracy (indeed, it amazes me that our own “Robber Baron” era didn’t send us along a different path).

Anyway.

In any event, I don’t intend to dwell on how easy it is to thwack the US. What’s interesting is how different folks come to this. That is, the sociology of becoming an intellectual terrorist. Intellectual being the key word here; I don’t think anyone who’s played this game wants to actually hurt the US. It’s serious (but necessary) business, obviously, to think these thoughts in the right context. So it’s not the emotional commitment, it’s the mental wrangling that’s interesting.

You come to red teaming with a fresh mind, but it’s also an uneducated one. You think about what you would do to hurt people, many people. And the answers you come up with, if you’re an academic, are surprisingly … academic. They are not always ‘flying planes into buildings’ sorts of answers. They’re more the things you see the Evil Mad Scientist doing in a Bond movie.

Over time, practice makes perfect. Plots become simpler, easier. More realistic.

But, amusingly, we / I seldom arrive at the same answer as the actual terrorists. Personally, I think our answers are better. More bang for your buck. But our answers don’t serve the needs of the terrorists quite as well. The symbolism of taking out the Twin Towers versus the strategic impact of other targets. And thus perhaps we scientists are not quite doing our job. I think other folks probably do a better job, and that is reassuring. I’d hate to think we’re essentially defended against low-rent Dr. Evil knockoffs, but not against the real thing.

- originally posted on Friday, July 9th, 2010

On the coming age of siRNA drugs

You all know what siRNAs are. Short, double-stranded RNA molecules that can regulate gene expression in a site-specific manner. Along with their various other natural and engineered counterparts (shRNAs, miRNAs, pi RNAs) it is anticipated that these reagents can be engineered to be effective drugs. Of course, we’ve been promised this before, in the guise of antisense oligonucleotides, which appeared not to pan out so well (but now are panning out surprisingly well; check out the ability of antisense oligonucleotides to alter splicing patterns and restore the function of mutant dystrophins in humans). In some ways, siRNAs can be thought of as son (or daughter) of antisense, but with greater potency because of the natural machinery that brings their base-pairing capabilities to bear.

The chief problem is delivery, as was the case for antisense oligonucleotides before them. You can ensconce them within liposomes or other lipid amalgams, you can tether them to delivery moieties like cholesterol, you can make peptide or protein complexes, you can even just rely on naked targeting and uptake (see the wonderfully named ‘gymnosis’ for details). These methods all have advantages and disadvantages, and there will doubtless be winners or losers in the end. But something will win. We will have sequence-specific gene modulation. And then it is hoped that the promise of molecular medicine originally seen in antisense oligonucleotides will be realized. We’ll be able to treat any disease, certainly any pathogen, by modulating gene expression in a sequence-specific manner.

But as a child of the 60s I have to wonder: what is the recreational potential of siRNA? Can we get down with them? And I have to answer: yes. Yes we can.

As an only mildly illicit example, there is a gene called MyoD that regulates muscle development. And there is a very interesting case of a small child in Germany who was born with a mutation in the MyoD gene. He was known locally as ‘Hercules,’ and for good reason. The kid was huge. At age 3 his limbs bulged with muscle. Now, imagine achieving the same effect by artificially knocking down the expression of MyoD, a single gene, with anti-MyoD siRNAs (again, assuming that the gnarly delivery problem is conquered). I have often suggested to my laboratory if research funding gets really tight we’re going to make up a big ol’ batch of the stuff, march down to the stadium, and make damn sure that our boys are much bigger than the OU players … for a profit, of course.

- originally posted on Friday, July 9th, 2010

On organismal augmentation

We are the only life we know. We have 20 canonical amino acids, 5 canonical nucleotides, and we relate the two via a genetic code where the exceptions prove the rule of its common origin. Boring.

But effective. Life is parsimonious because evolution is parsimonious. Shortest path to best fitness wins. In a fitness landscape that has foothills undulating up into mountains, that’s great. In a landscape where there is a distant Olympus, though, rising starkly from the plains, not so much.

This is where we come in. We are at a stage in our evolution where we can control evolution. How cool is that? And not on the bazillion year scale where organisms make oxygen which makes new organisms. No, we can begin to change the base set of chemistry right now.

I’ve been fascinated by this all my career, ever since I was a graduate student and read the coolest-paper-you’ve-never-heard-about: “Membership mutation of the genetic code: loss of fitness by tryptophan” (Wong (1983), PNAS, 80:6303; note to Jeff, you still need better PR!). This paper describes the evolution of the unSubtilis, a strain that can use 4-fluorotryptophan in place of tryptophan throughout its entire proteome. That’s right, a completely unnatural organism. At first I believed this result must just be wrong, but when I got my own lab I got the Wong strain, and we proved to our own satisfaction that it in fact grew well with only 4fW in the medium. We then tried to make an unColi of our own, but without the same type of success (Bacher and Ellington (2001), J Bact, 183:5414). Still, new chemistries are not evolutionarily inaccessible. Mostly they get adopted piecemeal (see selenocysteine or pyrrolysine for details), but it is possible to get them adopted whole hog.

What else can be done? Folks in the past have accommodated bacteria to heavy water; I heard a very interesting talk from Felisha Wolfe-Simon at the Geobiology meeting I was at about organisms that grow in high arsenic; and there are a few odd species on the planet that can incorporate fluorine into amino acids (although primarily for making natural products; I don’t think they go into proteins … yet).

Given the genomics revolution that is occurring (both sequencing and synthesis) the stage is set for organismal augmentation, for changing the base chemistry of life. Undoubtedly George Church amongst others will have something to say about this. But the real fun will be finding out what life does with its augmentation. I have no idea what new functionalities an organism that has fluoroproteins or As-DNA will come up with. But this will shift NeoLife to a Whole. Nother. Level. of the fitness landscape where it can slip and slide around.

-- originally posted on Thursday, July 1st, 2010

On origins

So today I’m in Golden, CO, of all places, waiting to give a seminar on “Synthetic Biology and Origins” (or maybe the other way around). This always brings up the odd place I occupy in the scientific spectrum on origins. I’ve pretty much been an origins of life biochemist most of my career, from my graduate work with Steve Benner to my development of in vitro selection with Jack Szostak to my own independent career, which has always to my mind been trying to invent life for fun and profit. So, I think I am somewhat qualified to speak on the subject. But what I have to say usually sets most folks’ teeth on edge, one way or the other.

To wit: there is no such thing as origins of life, because there is no such thing as life. Life is not a meaningful scientific term. It is a term for poets, not scientists. I think this began to become evident to me as I watched my peers unsuccessfully try to define this term, over and over. Now, this could mean that there is a very deep problem here, a problem whose solution has somehow eluded philosophers and scientists for thousands of years. Or it could just mean that it’s a stupid question. I have finally come around to the latter position.

Another way to examine this position is to observe how chemistry is taught relative to biology. While I am comfortable with the notion that electrons and atoms are at some level abstractions and fictions, they are at least well-defined abstractions and fictions, and can be manipulated within predictable frameworks. In the first few pages of a biology text, though, you never come across the definition of life. You may get an empirical description of living systems, but the underlying definition is never manifest. Instead, the framework for the study of biology is evolution, as it should be. But, interestingly, nothing about evolution implies the existence of a living system.

These views are unpopular both with normal folks, who of course find the notion that nothing is ‘alive’ to be counterintuitive at best and blasphemous at worst, and with scientists, who are queasy with them because they intuit the truth of the matter, and don’t like having to take a position that the lay public would adjudge offensive.

Invariably when I bring these issues up I am challenged with an existence proof: there, what’s that, then? That bug crawling, that plant growing? Life is apparently like pornography: you may not be able to define it, but you know it when you see it. And my reasonably well thought-out reply is: you are talking about replicators, and these replicators take different forms and have different degrees of complexity. From this vantage, the age-old saw about whether a virus is ‘alive’ melts away: viruses are replicators, they use cells as their environment, just as we are replicators that live off of an environment that includes air. Viruses cannot replicate without someone else giving them a ribosome; we cannot replicate without air. And, yes, I’m perfectly happy with crystals replicating in their little niche, and computer programs in theirs. It is the description of the replicator that is important, not any supernatural patter attached to a given class of replicator.

- originally posted on Thursday, July 1st, 2010

On the threat of synthetic biology

I’m on record as suggesting that synthetic biology does not constitute much in the way of a biothreat (Nature Biotechnology, December, 2009, pp. 1071-1073). However, this does not stop many of the practitioners of this ‘discipline’ from declaring that the sky is falling. This sort of raises the question as to what synthetic biology actually is, and how it differs in some significant way from what has come before. It is hard to get a consensus definition of what the term is or what the field constitutes, and this is likely because ’synthetic biology’ is more buzzword than meaningful term. What we now call ’synthetic biology’ used to be called biotechnology: the purposeful alteration of biological sequences and organisms for desired functions. All that has really occurred is that DNA synthesis technology has matured to the point where this can be done on a larger scale than previously.

But the larger scale is sort of not the point; the impact of genetic changes is. And in this regard, biotechnology is as dangerous as it ever was. Which is to say: very, very dangerous. Any molecular biologist who turns their attention to ‘red teaming,’ trying to figure out what bad people would do if they had the same skill set as the molecular biologist, quickly comes to the conclusion that many of us should already be dead (or, more to the point, the economy should be in even greater tatters than it is now). It’s just too easy.

Which raises the question: why aren’t we dead? The answer is not: we hadn’t yet invented synthetic biology. Very bad things can be done with very simple alterations, or even (perhaps especially) with no alterations at all. While the press and the scientific community decried the total synthesis of poliovirus as some sort of Hellish milestone, this was long preceded by Pim Stemmer showing how shuffling HIV-1 could generate some unsettling viral phenotypes (and somewhere in our own archives are theoretical suggestions as to what might be done with pox viruses). Heck, if anything, the focus on synthetic biology is a welcome distraction, in that perhaps our adversaries will think that they need to fill their caves and lairs with Venter-style DNA synthesis combines in order to do us any damage. That would be a relief.

What’s unfortunate is that the hysteria over synthetic biology seems to be driving policy and funding. And this in turn suggests an unsettling feedback loop between the experts in the non-field, and the sources of funding for the non-field. Or so it appears

- originally posted on Thursday, July 1st, 2010

On Fabs and DNA hacking

I have a tendency to be too limited in my vision. Back before the human genome was sequenced, I really couldn’t see the point of it. And more recently, as we’ve begun to contemplate the ease with which genome synthesis can be carried out, I again sometimes fail to see the importance. My limitations primarily have to do with having to deal with the nitty gritty of technologies that are right in front of my eyes, and therefore failing to step back and see what the future might bring. It’s easy to dream, and hard to do.

That said, we may actually be modestly ahead of the curve for a change. Not much, but a little. Recently, we’ve set up a DNA Fab at the Applied Research Labs of the University of Texas at Austin. From my vantage, it’s a remarkable facility, capable of the de novo synthesis of upwards of 100x 1 kb genes / week. Now, this is nothing compared to what many companies can do, but for our little operation it’s quite an achievement. We’ve even managed to develop some relatively novel protocols for DNA synthesis, and have developed a pretty decent ‘how to’ manual for setting up a Fab. For right now, it’s incredibly useful for our projects that center on antibody development, biosensor design, and synthetic biology in general. That said, it will likely soon be displaced by chip-based synthesis protocols.

But that raises the interesting question of who owns DNA synthesis. Back in the day, every lab had a DNA synthesizer. My lab started with a one-port machine that I miss dearly, in part because we could change out any piece of the plumbing on a moment’s notice. Then, DNA synthesis migrated to core facilities, which typically had one or more four-port machines. And then economies of scale drove the business into companies, and all of the old synthesizers slowly faded away. It’s rare now that you find a lab that does even a little of its own synthesis.

Of course, anyone who wants to do their own DNA synthesis can still buy such machines, especially used ones. And in that regard, it’s not like ‘private’ DNA synthesis is ever going away. But the opportunities for individuals to make their own DNA, especially at the scales that we’re now operating at, are few and far between. It is unlikely that we will ever face a situation wherein an individual can synthesize a virus without some commercial entity being cognizant of the oligonucleotides that are being ordered. The fantasies of the DIY crowd will pretty much always be subject to some sort of oversight. This is, in my opinion, a good thing. Still, it’s a little weird to think that DNA and biology have been commoditized to the point where hacking is a thing of the past before it even gets off the ground.

- originally posted on Thursday, July 1st, 2010