It’s 2012.12.22: Time For a New Doomsdate

Posted on 2012.12.21 by Alan

It’s about 30 minutes after the Winter Solstice now, which means the ancient Mayan calendar has officially ticked over to a new year, and thousands of doomsayers are looking a bit foolish right about now. If you’re one of them, don’t despair: I have the updated doomsdate right here for you.

Yes, that’s right, some Wise Old Ones Who Must Have Known Everything Because They Lived A Long Time Ago and Spoke Cryptically have entrusted me with their Great Secret. I know the true final date, the End of Time, the Last Day.

You see, I bought a date stamp about twelve years ago, and I knew right away that it was more than a mere office supply. Sure, this stamp would let me mark dates on invoices I sent, checks I received, bills I paid, and orders I placed or canceled, but it also encoded an end date. Rather than fill all of the available “year” spaces, the Wise Old Ones filled only a subset of them. Why?

Obviously, they meant to communicate something. And the latest year they included on this artifact was 2013. I can stamp all I like until the final day of the final month of 2013, but after that, nothing. They presupposed that nobody, anywhere, would ever want to stamp anything after that date.

39 December 2013: The world will be backordered.

39 December 2013: The world will be backordered.

My own random actions since 2000 have decoded the rest of the message, and revealed our civilization’s bizarre fate. I have answered, canceled, billed, charged, checked, delivered, entered, paid, received, and shipped various stampable items over the years, but there is one option that I have never, ever felt the need to exercise. That action is obviously being saved for last. Very last.

Carefully advancing the stamp to its last possible date, and aligning the action wheel to its only un-inked position, I reveal the terrifying truth. On 39 December 2013, the world will be backordered.

Prepare yourself.

Posted in Uncategorized | Tagged , , , , | 1 Comment

Do These Stripes Make My Nanoparticles Look Weird?

Posted on 2012.12.05 by Alan

There’s something interesting happening in the staid world of peer review these days, and a recent set of posts on another site renewed my hope that it could be a positive trend. Raphaël Lévy at the University of Liverpool starts off the first post this way:

Challenging published results is an onerous but necessary task. Today, our article entitled Stripy Nanoparticles Revisited has been published in Small, three years after its initial submission to this journal (3/12/09) and about three and a half years after the first submission (to Nature Materials, 21/07/09).

As its title indicates, the article challenges the evidence for the existence and properties of “stripy” nanoparticles.

That, and a followup post from another nanoparticle researcher, are interesting reading just for the underlying science. Both researchers do a good job describing the techniques for creating and studying these very tiny structures, which could be useful for all sorts of cool engineering tricks. One intriguing characteristic of these nanoparticles is that they can apparently cause certain types of molecules to self-organize into precise patterns of stripes on their surfaces. At least, that was what earlier work had shown. Lévy, however, thinks this stripy pattern is an artifact, the microscopic version of an optical illusion.

On its surface, this looks like a very small controversy in every sense of the word. Who cares whether a few minuscule spheres mixed with some odd chemicals are striped or smooth or bumpy or dancing the hokey-pokey? I’m certainly not qualified to take a stance on the issue, and it’s hard to see any immediate relevance to my life, but seemingly arcane disputes like this drive much of the scientific enterprise. Get the details wrong on stripy nanoparticles, and maybe we can’t build the next generation of computers. We won’t know why it matters until suddenly it does.

The classic quality control system for scientific facts is peer review, in which scientists submit their work to journals, which distribute the paper to anonymous colleagues of the author for independent analysis. If the author’s professional competitors agree that the new findings are significant and probably correct, then the journal will publish the paper. Peer review always has been a deeply flawed system, plagued by academic politics, errors, and inefficiency, but until recently nobody could come up with a better one.

The World Wide Web changed that by design. It’s easy to forget that the whole online ecosystem we now take for granted originated from a scientist’s frustration with paper-based publishing. YouTube, Amazon, Facebook, and their ilk are merely side-effects of a platform built expressly for reporting science. Now, decades later, researchers are finally starting to appreciate the full depth of what the Web can do for peer review. Lévy and his colleagues are part of that trend. Ironically, they still have to combat the perception that the internet is somehow an inappropriate venue for this. A system built for science is now synonymous with shopping, ranting, and porn in many people’s minds.

What I find most interesting about the stripy nanoparticle conversation is that it has the generally civil tone, moderate pace, and narrow scope of classical peer review. There are lots of other examples of this type of “post-publication review” online, but the ones that draw attention are usually as much about public relations as they are about data. Reading the comments on Lévy’s blog, I’m mostly struck by how thoughtful and well-informed they (mostly) are, and how many of the participants genuinely seem to care more about getting the right answer than winning. That’s how it’s supposed to be done. That’s science.

Posted in Uncategorized | Tagged , , | 2 Comments

High Fructose Corn Syrup: Hard Questions, Easy Answer

Posted on 2012.11.29 by Alan

If you’ve read anything about obesity and nutrition in the past few years, or paid any attention to food packages in the supermarket, you’re aware that there’s a bit of a controversy surrounding a sweetener called high fructose corn syrup, or HFCS. By “a bit of a controversy,” I mean a continuously escalating shouting match involving two extreme, opposing views and a whole lot of ambiguous data.

In one corner, we have a few researchers and a lot of foodies who argue strenuously that HFCS is a major cause, if not the sole cause, of the global pandemic of obesity, diabetes, and “metabolic syndrome.” Opposing these advocates is a multi-billion-dollar government-subsidized food processing industry, heavily invested in producing HFCS-laden products, claiming that the stuff is completely harmless and safe. In between are a lot of scientists genuinely trying to figure out a knot of apparently conflicting study results. Meanwhile, the general public would really appreciate some clear answers before it’s time to serve dinner.

Biochemical conversion of fructose to glycogen.

Fructose, in its usual role of torturing biochemistry students while forming glycogen.

The underlying questions in this debate are very hard to unravel, but this is an unusual instance where most of us can simply disregard all of that and make a simple, obvious choice based on sound risk analysis. Here’s why.

The scientific evidence on HFCS is all over the map, contrary to what advocates on both sides would have you believe. There is no clear proof that this stuff is safe, and no clear proof that it isn’t. Instead, we have a whole lot of suggestive, circumstantial evidence that HFCS might be bad for you, and a whole lot of suggestive, circumstantial evidence that it might not. Many anti-HFCS advocates point to the timing of the sweetener’s introduction, as it became prevalent in the global food supply at exactly the same time we started porking up. On the other hand, the same period saw widespread adoption of cable TV and then the internet, a decline in manufacturing and rise in sedentary work in developed countries, a steady decrease in sleep, and so on. Trying to look at this in more detail, a team of scientists recently completed a huge analysis of multinational data sets, and found that nations with high HFCS consumption rates also have relatively high rates of obesity and metabolic syndrome, even when matched for other traits. However, HFCS consumption could simply be a surrogate marker for processed food consumption, and in any case this particular study doesn’t prove much.

Mechanistic analyses have been similarly ambiguous: feeding rats a diet rich in HFCS can cause them to gain weight, but rodent metabolism differs radically from human metabolism. The most rigorous studies in humans have involved isocaloric diets with either HFCS or sugar as the primary sweetener, and found no difference in weight gain. Isocaloric diets are misleading, though. Outside of controlled clinical trials people eat until they’re full, and there are sound biochemical reasons to believe that our satiety circuits may not register the excess fructose in HFCS the same way we register the breakdown products of sucrose. If HFCS-laden food makes you feel less full for a given number of calories, it could prompt you to eat more. But that’s just a theory.

These mud-clear data haven’t stopped some folks from taking strong stances on the issue. I’ve even been guilty of overinterpreting studies that agreed with my preconceived notions at the time, and my wife is entirely sold on the idea that HFCS is liquid evil. More broadly, authors of papers like the new multinational analysis haven’t shied away from hype-enriched press releases, and of course the deep-pocketed industry making the product is guilty of exactly the same behavior. Both sides repeat their mantras (“It’s nutritionally equivalent to sugar,” “Is not,” “Is so…”) while ignoring all evidence to the contrary. The stakes are astronomical, so the screaming is quite loud.

As I said, though, there’s a very easy way out of this discussion. HFCS contains no essential nutrients. It occurs in no staple foods. It is completely unnecessary in anyone’s diet. Unlike some other controversial foods, there is absolutely no reason to consume this one. So don’t. This is a rare case where the risk-benefit analysis contains absolutely nothing in the benefits column. That means any risk, even a theoretical one, justifies avoiding this substance.

It may sound like I’m endorsing the “HFCS is bad” position, and certainly I have domestic reasons to go along with that, but I’m not. I honestly don’t care whether HFCS is bad for me. All I need to know about it is that it’s a diagnostic marker for junk food: if the product contains HFCS, it contains empty calories, was manufactured as cheaply as possible, and almost certainly tastes fake. Some of the same criticisms apply to sugar, but not all. Sugar is an ancient and sometimes necessary preservative, it’s never used as a low-cost option where HFCS would do, and it’s quite hard to run a kitchen without it. I can only cut back on sugar, but I can avoid HFCS entirely.

The dietary impact of eliminating HFCS is all good, even if we ignore the recent studies. Sodas and other sweets made with sugar are uniformly more expensive than similar products made with HFCS, so there’s an instant incentive to cut back on them. Highly processed entrees may contain it, but a meal made from scratch (which often cooks up just as fast as a TV dinner and tastes vastly better) doesn’t. Whether or not HFCS bypasses my satiety circuits, I’ll probably put fewer calories on my plate when I’m avoiding it, and the calories I do consume will automatically skew a bit more toward the nutrient-rich foods every dietitian advocates.

“But what about the poor?” comes the cry in every food discussion. Well, what about them? In the developed world, the days of the starving poor are long gone. Now, poverty correlates quite strongly with obesity. If avoiding HFCS prompts poor people to consume fewer but more nutrient-rich calories, that’s a big step in the right direction. The picture is more complicated in developing countries, many of which are struggling with simultaneous epidemics of obesity and starvation, but even there it’s unlikely that the empty calories of HFCS are helpful. People need food, not Coca-Cola.

To be clear, I’m not advocating any kind of legal ban on HFCS. Legislation and regulation should always rest on sound evidence, and we don’t have that here. However, if more people avoid this sweetener by choice – and both industry data and package labeling suggest that’s the trend – a much more powerful force will decide the issue: the law of supply and demand.

Posted in Uncategorized | Tagged , , , | Comments Off

Single Molecule Determines Complex Behavior, Say Scientists

Posted on 2012.11.15 by Alan

In a groundbreaking new study, scientists at Some University have discovered that a single molecule may drive people to perform that complex behavior we’ve all observed. Though other researchers consider the results of the small, poorly structured experiment misleading, a well-written press release ensures that their criticisms will be restricted to brief quotes buried near the bottoms of most news stories on the work, if they’re included at all.

“This is a real game-changer for our understanding of this complex behavior, which has affected so many lives,” said Wannabe Famous, PhD, who directed the study. Dr. Famous describes the results, which were hyped relentlessly to journalists for a week before being published in today’s issue of A Scientific Journal, as “the Holy Grail of a field that has been trying to link this single molecule to a complex behavior for decades.”

Though he cautions that the findings are too preliminary to be a basis for any specific recommendations, Dr. Famous says that drugs targeting the single molecule could some day help treat patients displaying this complex behavior. “It’s a controversial issue, because of course complex behaviors are what make us human, or at least animal, but for people dealing with the broken marriages, inadvisable purchases, and stained kitchen tiles that this behavior can cause, a workable therapy would be a blessing,” said Dr. Famous.

The new results add to a growing body of evidence that all of human nature rests on a handful of chemical reactions. Researchers initially believed that the widely-acknowledged link between testosterone and carpentry was a fluke, but studies connecting dopamine to scuba diving, and oxytocin to the production of cat videos on YouTube, have drawn more attention to the seductive power of oversimplifications. “We’re really standing on the shoulders of giants,” said Famous.

Other scientists agree, at least when quoted selectively. “Famous’s result is just unbelievable,” said one researcher, who asked not to be named after seeing a draft of this article.

Nonetheless, controversy persists in the field, especially among those whose statements are harder to misconstrue. “This single molecule has a bunch of different functions, most of which we probably don’t even know yet, and there are thousands of other signaling molecules circulating in the body at any given time, so claiming that it’s the sole cause of this complex behavior is just absurd,” said Grumpy Skeptic, PhD.

But Famous remains undaunted, and argues that his results will ultimately stand on their own whether other researchers replicate them or not. “Ten years from now, if you ask someone whose science education consists mainly of skimming news stories, I’m sure they’ll confirm that this single molecule causes this complex behavior,” said Famous.

Posted in Uncategorized | Tagged , , | 12 Comments

Political Science

Posted on 2012.11.01 by Alan

As the shoutfest The Onion fittingly dubbed “The War for the White House” staggers towards its storm-soaked climax next Tuesday, there’s one fundamental question that I don’t think has really been answered yet:

Why are scientists such raving liberals?

Obama Banner

Yes, science moves in that direction too.

We can’t deny that we look that way to the general public. Nature, which is to science what the Wall Street Journal is to investment banking, unabashedly endorsed President Obama for re-election. Sixty-eight Nobel laureates signed an open letter making the same endorsement. If you follow scientists or science journalists on Twitter, your feed will seldom go an hour without someone advocating Democratic policies or candidates. And by the highly polarized standards of our time, voting for Democrats automatically constitutes raving liberalism, as surely as voting for a Republican is diagnostic of reactionary wingnuttery.

Never mind that “scientists” are far from homogeneous. We’re a group whose principal unifying traits are independent thought, distrust of authority, and a love of intense, arcane arguments. We will agree – slowly, grudgingly – to certain broad, general principles, but only in the face of overwhelming evidence. Even then, the “scientific consensus” inevitably contains thousands of small but intense disagreements about the details. Virtually every biologist worthy of the title will concur that complex life evolved from simpler life, and continues to do so, but if you ask whether this particular species diverged sooner or later than that one, or even what the word “species” means, you’ll immediately see taxonomists disemboweling each other. So how can we possibly have a unified political agenda?

We don’t, of course. Talking to scientists is a big part of my job, and when specific policies come up, the conversation inevitably reveals diverse and unpredictable opinions. Scientists in industry sometimes sound like good Republicans, advocating smaller government, less regulation, and unrestrained markets, while academic researchers sometimes favor more government funding, stronger regulations, and less industry involvement, like stereotypical Democrats. Other times it’s the reverse, and the same scientist commonly appears on different sides of the aisle on different issues. Like taxonomists debating the proper classification of a grasshopper, we’re all over the map.

There’s also some diversity in scientists’ assessments of the two major political parties, but in broad, general terms the group leans toward the Democrats. Some have theorized that this is because Democratic candidates are more likely to understand (or at least purport to understand) the complexity and nuances of major policy questions, whereas Republicans prefer pat slogans that oversimplify the issues, and scientists understand that oversimplification is dangerous. I think that’s bullshit. Bumper stickers that proclaim “Healthcare is a human right” are no less jingoistic than “Abortion stops a beating heart.” Both are willfully deceptive oversimplifications.

Nor does either side’s constituency have a monopoly on the rational treatment of data. If you like to ignore the overwhelming evidence that humans are changing the global climate, odds are you vote with the red states. But if you irrationally oppose genetically modified crops, then I’ll bet the donkey is your mascot. Anti-vaccine advocates, animal rights groups, and the anti-psychiatry movement also draw mostly from the left side of the aisle. Indeed, I suspect that if we held a big conference for everyone who advocates profoundly irrational policies, we’d draw a solid Democratic majority.

Given the blatant stupidity on both sides, you might expect scientists to just throw up their hands, pick randomly, and say “don’t blame me, I voted for Kodos.” I know some who do. There is, however, one crucial difference between the two parties, at least in their current incarnations. Considering what I said a few paragraphs ago, I certainly wouldn’t presume to speak for all scientists, but this difference is the main reason my own voting record has favored Democrats, and I suspect others may have reached similar conclusions.

Political parties are like dysfunctional families. Everyone has a few crazy cousins somewhere, so the question is how to deal with them. The Democratic party tolerates but marginalizes its anti-science crusaders. The Republican party hands them the keys. That’s why the Bush administration and Republicans in Congress neutered the EPA, obstructed any meaningful environmental legislation that came up, and hamstrung public health agencies and some branches of research. Their crazy cousins didn’t like what the science was saying, so they banned it. When Obama was elected, he came into office with a commanding majority in Congress. If the two parties were truly equivalent in their stupidity, we would have seen vaccination, genetically modified crops, and animal research in the crosshairs. Instead, the Democrats nodded and smiled at their crazy cousins, then went about enacting (mostly) rational and moderate policies in all of those areas.

I don’t think this comparative Democratic rationality is deliberate. Instead, it stems from the way the two parties operate. The GOP is a carefully engineered political machine, which is why it’s so frighteningly efficient when its candidates gain power. By grabbing a few critical levers, a small, unhinged minority can take control of the whole juggernaut, and that’s exactly what we’ve seen in recent years. The Democratic party is more of an amoeboid organism, sending out pseudopodia in all directions, averaging the inputs from innumerable signals, and finally crawling in a specific direction for a short distance before repeating the whole cycle. It’s slow, inefficient and cumbersome, but very unlikely to run off the rails.

If that sounds like faint praise, it’s because it is. Should the Republicans ever hand the controls over to scientists, do a teardown on their platform, and adopt consistent, evidence-based policymaking as their primary ideology, I’d be thrilled to join them. Until then, I’ll be voting for these folks.

Posted in Uncategorized | Tagged , | 1 Comment

From Immuno-PCR to Peptoids: Why Great Ideas Sometimes Aren’t

Posted on 2012.10.31 by Alan

From the inbox last month:

Dear Dr. Dove:

Just curious. Do you really think Kodadek’s Cell paper is a good piece of work? The response of the science community to this seemingly amazing news is silence. This usually means that the results of the paper are odd.

Wang fan

Thanks for your note, Wang, and I’m sorry it’s taken me a month to get back to you. This question touches on some much broader issues in science and science journalism, and I wanted to take the time to put together a proper blog post about it. For readers who don’t know the background, here is my original post about Kodadek’s work, in which I unabashedly raved about a novel technique for discovering new disease biomarkers.

I stand by that assessment. The researchers performed an extremely clever experiment, it apparently worked, and they followed up on it pretty carefully. That’s what science is supposed to be about.

So why isn’t everyone using Kodadek’s strategy to find a slew of new biomarkers already? I can think of a few possibilities. One, of course, is that the technique might be a lot harder to perform than the paper suggested. Perhaps it yields inconsistent results for different diseases. Perhaps there just aren’t good biomarkers for some of the diseases we want to study. Or perhaps people are all over this technique, and we just haven’t seen the papers yet – it hasn’t quite been two years, and these studies would take some time. It’s also possible that the method just isn’t as useful as it first seemed. These sorts of problems trip up new ideas a lot more often than even most scientists realize.

Consider, for example, the tangled tale of another biomarker detection scheme: immuno-PCR. Developed by Charles Cantor’s group way back in 1992, immuno-PCR uses the highly effective signal amplification of polymerase chain reaction (PCR) to detect proteins. The technique was supposed to solve one of the biggest problems in biochemistry at the time, which was identifying and quantifying proteins that are present in vanishingly small quantities in a sample, which certainly describes many promising disease biomarkers. Immuno-PCR was much more sensitive than the best available competitor, a technique called enzyme-linked immunosorbent assay (ELISA), and more sensitive protein assays really sounded like just the thing. The new method was poised for greatness.

But it flopped, or at least went to sleep for awhile. In 2008, I wrote a feature article for Bioscience Technology magazine about protein detection methods, and pretty much everyone I talked to agreed that immuno-PCR was a disappointment. Indeed, several companies were trying to develop a replacement that would work better. It turned out that immuno-PCR was just too hard to do properly, so most users gave up on it.

Similar problems befell David Ward and his colleagues at Yale University, who developed an equally clever protein detection system called the rolling circle immunoassay in 2000. Instead of PCR, Ward’s assay relied on a type of amplification called rolling circle replication, which many viruses use. This elegant new technique blew the doors off ELISA; the investigators could detect proteins at single-molecule sensitivity. Rolling circles were supposed to succeed where immuno-PCR had failed, but instead they also landed in the bin.

Some of the techniques developed since then have fared slightly better. A company called Nanosphere, building on work by Chad Mirkin and colleagues at Northwestern University, now has FDA approval for high-sensitivity diagnostic tests based on a nanoparticle detection system that uses DNA “barcodes” to identify individual proteins in a sample. Nanosphere’s technology apparently offers the sensitivity of techniques like immuno-PCR and rolling circles, without the same technical headaches.

While successive groups of scientists were working on these assays, though, advances in completely different protein analysis techniques made antibody-based detection somewhat less relevant. The past decade has seen astonishing advances in protein mass spectrometry, which allows researchers to identify and quantify proteins without having to make antibodies against them first. Why bother with DNA-bound immunological probes when you can simply feed your sample into a box and read a list of the proteins in it on your computer screen?

Meanwhile, we’ve learned more about protein-based assays, especially in medical testing, and it turns out that greater sensitivity isn’t always a good thing. Barcoded nanoparticles can detect previously undetectable levels of prostate-specific antigen (PSA), for example, but a growing body of evidence suggests that PSA testing does more harm than good. Making a bad test more sensitive only makes it a worse test.

Anyone who’s been a science journalist for more than a few years has probably collected a whole slew of similar stories: results that just didn’t pan out. That’s why I always try to discuss the limitations of a new paper as frankly as possible, even in the midst of an unabashed rave.

So what happened to peptoids? It’s too early to tell. Even if the technique proves troublesome, it represents a fresh approach to a question that currently looks important: what bloodstream biomarkers can we measure to diagnose and monitor chronic diseases such as Alzheimer’s and cancer? 18 months ago, peptoids looked like they might be a really cool strategy for exploring that topic. Maybe they still are.

References

1: Sano T, Smith CL, Cantor CR, “Immuno-PCR: very sensitive antigen detection by means of specific antibody-DNA conjugates,” Science, 1992 Oct 2;258(5079):120-2.

2. Schweitzer B, et al., “Immunoassays with rolling circle DNA amplification: a versatile platform for ultrasensitive antigen detection,” Proc Natl Acad Sci U S A. 2000 Aug 29;97(18):10113-9

3. Hill HD, Mirkin CA, “The bio-barcode assay for the detection of protein and nucleic acid targets using DTT-induced ligand exchange,” Nat Protoc. 2006;1(1):324-36

4. Thaxton CS, et al., “Nanoparticle-based bio-barcode assay redefines “undetectable” PSA and biochemical recurrence after radical prostatectomy,” Proc Natl Acad Sci U S A. 2009 Nov 3;106(44):18437-42. Epub 2009 Oct 19

Posted in Uncategorized | Tagged , , | Comments Off

Making Your Experiments Easier to Digest

Posted on 2012.10.18 by Alan

One of the great things about being a science journalist is being among the first to hear about technologies that are cool, useful, and/or downright weird. Today, for example, I learned that the world’s leading manufacturer of artificial laboratory stomachs has released a fascinating new series of videos. You can check out their channel on YouTube, where you’ll find such gems as this brief instructional piece that covers – quite literally – the care and feeding of your artificial laboratory stomach:

Posted in Uncategorized | Tagged , , | Comments Off

Pseudomonas: Even More Bad-Assed Than We Thought

Posted on 2012.09.21 by Alan

The first time I met the genus Pseudomonas, I was a brand-new graduate student doing a rotation in David Figurski’s lab at Columbia University. Dave works on “promiscuous” plasmids that can move to many different species of bacteria. These plasmids pay their rent by providing multiple antibiotic resistance genes and other goodies to the bugs that host them. In that lab, we commonly cultured new strains with three or four different antibiotics in order to select for particular plasmids. Novice that I was, it seemed to me that such cultures would be pretty foolproof in terms of contamination – I mean, how many “wild” bacteria could live in such a drug-laden soup?

Pseudomonas aeruginosa, for one. It wasn’t long before I managed to contaminate a plate with something that grew bright green colonies and had a weird grape-like odor. A senior grad student in the lab diagnosed it immediately. “But how can it survive on there?” I asked. “It’s Pseudomonas,” he laughed.

Pseudomonas killing another bacterium with secreted toxins.

The last thing you see: P. aeruginosa (red) secretes toxins into another bacterium (green/blue), causing its cell wall to fall apart. Image by James Easter.

While many bacteria pick up drug resistance genes here and there through mobile genetic elements such as plasmids and transposons, P. aeruginosa has resistances baked right into its genome. It carries multiple drug-specific resistance genes as well as general-purpose pumps that throw antibiotics out of the cell before they can even act.

One Pseudomonas cousin, now known as Burkholderia cepacia, takes this tough-guy act a step further; it can actually use penicillin as a food source. Imagine hornets passing around a can of Raid so they can take long pulls from it while commenting on its pleasant flavor, and you’ve got the general idea. These are some seriously bad-assed bugs.

Given all that, perhaps it shouldn’t come as a surprise that P. aeruginosa is also covered in venomous spines. That was the conclusion of a paper published last summer by researchers at the University of Washington, and discussed in an accompanying News & Views article in Nature.

The authors start off the paper with an excellent description of the microbial world:

Competition for niches among bacteria is widespread, fierce and deliberate. These organisms produce factors ranging in complexity from small diffusible molecules to multicomponent machines, in order to inhibit the proliferation of rival cells.

It’s a jungle down there at the micrometer scale, and P. aeruginosa is the honey badger.

This is a heavily armed conflict on all sides. While we often think of antibiotics as brilliant products of medical research, microbes invented them. Penicillin is just a fungus’s way to get ahead of its bacterial competitors; penicillin resistance is the bacterial side’s countermeasure. We’re naive newcomers to a battle that’s been raging for billions of years.

One of the more sophisticated siege machines in play is called the Type VI secretion system, a set of proteins found in many Gram-negative bacteria. The Type VI system injects proteins from one cell directly into another when they touch, in a manner similar to the way some bacteriophages transfer their genetic material into their hosts. That similarity could be a case of convergent evolution, in which form followed function, or the bacteria might have ripped off the mechanism directly from an ancient phage infection that went awry. I favor the latter explanation, largely because it fits so well with the general Pseudomonas attitude. Scrapping an infecting pathogen to build a weapon just sounds like something it would do.

In P. aeruginosa, the Type VI system exports at least three proteins, called Tse1, Tse2, and Tse3. All three, the new paper explains, are poisonous to other Gram-negative bacteria. Tse1 and Tse3 attack the peptidoglycan structure that lies in the periplasmic space between the outer and inner membranes of Gram-negative cells, causing the cell to fall apart or lyse. Earlier work had shown that Tse2 is toxic when it enters the cytoplasm, but it’s not clear exactly how it kills. When P. aeruginosa contacts another Gram-negative bacterium, it can use its Type VI secretion system to inject these toxins into the periplasmic space, killing off its competition so it can colonize a new food source.

That’s all well and good, but there’s a problem: the Tse proteins can also kill P. aeruginosa. To solve that, the bacteria carry antidotes, called Tsi1, Tsi2, and Tsi3. Each poison/antidote pair is expressed from a bicistronic operon (two genes transcribed from a single promoter), so whenever a cell manufactures the poison, it simultaneously produces the antidote for itself.

If Pseudomonas is producing both poison and antidote, though, why not just secrete the poison into the environment, antibiotic-style, rather than inject it through direct contact? It could be that these particular toxins don’t work well when diluted in the surrounding fluid, or that the whole toxin-plus-injection system evolved as a complete setup. Evolution doesn’t analyze a problem and calculate the most efficient way of doing things, it just tries out solutions until something works, and this works. It’s also possible that Pseudomonas is playing a more sophisticated game that we still haven’t fully uncovered. Transfering a toxin through direct contact could allow the bacterium to perform some kind of recognition step so that it won’t inject its brethren. Bayonets are less likely to cause collateral damage than bombs.

Whatever Pseudomonas is up to, it’s certainly a good system to keep studying. Besides being a pathogen in its own right, especially in patients with cystic fibrosis or immune deficiencies, this genus provides a nice sampling of the kinds of adaptations bacteria have evolved to survive in ferociously competitive environments. If it shows up as a contaminant in your lab, though, just throw those plates into the autoclave. That’s one thing even Pseudomonas can’t survive – yet.

1. Alistair B. Russell, Rachel D. Hood, Nhat Khai Bui, Michele LeRoux, Waldemar Vollmer & Joseph D. Mougous (2011). Type VI secretion delivers bacteriolytic
effectors to target cells, Nature, DOI: 10.1038/nature10244

Posted in Research Blogging | Tagged , , | 1 Comment

Decoding ENCODE

Posted on 2012.09.05 by Alan

Today, a scientific collaboration called the Encyclopedia of DNA Elements (ENCODE) published some of its data. When I say “collaboration,” I mean more than 400 scientists working in 32 different labs, and when I say “some of its data,” I mean over 1,600 experiments involving 24 types of analyses on 147 cultured cell lines.

A typical ENCODE experimental result.

A typical ENCODE experimental result. Links to the original figure.

ENCODE didn’t publish this massive data set in a paper. They published it in 30 papers that came out simultaneously in three journals, plus additional commentary elsewhere. To help people make sense of this information glut, Nature, the main publisher, set up a special web page where all of the papers are freely available, released an iPad app that lets users explore the results through different “threads” of inquiry, and held a press conference that featured several of the consortium’s principal researchers as well as an interpretive dance performance inspired by the results. Yes, really.

As regular readers know, I’m always ready to call out publishers who engage in excessive hype. In this case, though, I think Nature‘s hoopla is entirely appropriate. This is a $185 million project that’s trying to figure out how humans work at a molecular level, and the current batch of publications presents both a rough sketch of an answer and a whole new list of big questions.

Most science news stories on ENCODE will probably begin and end with an observation about “junk DNA,” and how the new data apparently overturn the notion that most of the human genome is just taking up space. Perhaps acknowledging that this is the most easily-digested result, the press materials and many of the commentary articles highlight it. Molecular biologist Joseph Ecker puts it this way in his synopsis:

One of the more remarkable findings … is that 80% of the genome contains elements linked to biochemical functions, dispatching the widely held view that the human genome is mostly ‘junk DNA.’ The authors report that the space between genes is filled with enhancers (regulatory DNA elements), promoters (the sites at which DNA’s transcription into RNA is initiated) and numerous previously overlooked regions that encode RNA transcripts that are not translated into proteins but might have regulatory roles.

But neither that result nor any other individual piece of the data is really the main point. What matters about ENCODE is the totality of it, and what the scale of the data says about the future of biology.

When the Human Genome Project released its draft sequence 11 years ago, it was a bit like Deep Thought reporting that the answer was in fact 42. By itself, the genome sequence told us that we only had about 20,000 genes, and that most of our DNA didn’t look like it had any function at all. There was obviously a lot more going on than we’d be able to glean just by looking at the sequence.

ENCODE is a follow-up project, in which researchers used a huge variety of techniques to probe the functions of all of the parts of our DNA, not just the segments that contain obvious genes. They looked for enhancers that can control the expression of genes in other parts of the genome. They screened all of the RNA in cells to find new pieces of micro-RNA, a type of gene-controlling molecule we didn’t even know about when I went to graduate school. They tested which parts of the genome were wrapped up in chromatin, a sort of deep storage system, and which were open for business in different types of cells. And on and on. In short, they examined what every piece of the genome was doing under as many different conditions as they could.

Besides finding that most of the genome is probably doing something to earn its keep, ENCODE has illuminated the scope of the problem biologists now face. It’s huge.

A graphic accompanying Brendan Maher’s excellent news feature on the project shows what ENCODE has accomplished so far, and how much work remains just to finish its initial phase. For example, the investigators have looked at only 120 of an estimated 1,800 transcription factors, proteins that control gene expression directly, and they’ve only looked at those factors in a subset of the cell lines they set out to study. That one snippet of the work produced a massive amount of information by itself.

Even after ENCODE finishes, what we’ll have will be more of a pamphlet than an encyclopedia. Cultured human cell lines are a great tool for laboratory studies, but they only partly mimic the behavior of the cells that make up a real human, which in turn vary from person to person and within a single person over time. ENCODE is giving us a two-dimensional view of a system that’s at least five-dimensional. That’s not to minimize the project; the team has made astonishing progress, but it’s just a start.

After doing the rest of the cultured cell experiments, biologists will have to figure out the results, which raises a whole new problem. I can’t tell you what all of the ENCODE data mean. Neither can the people who generated them. Besides the 30 new papers (and their supplementary online sections), the project has also produced databases, software, and other analytical tools so scientists can dive into the results directly. The conclusions of the new papers are just the bits that the experimenters thought were most interesting. As happened with the human genome sequence, people will be digging new publications out of these data for years.

Right now, we’re like astronomers looking at millions of smudges of light we can see with a new telescope, and it’s just dawning on us that those aren’t stars. They’re galaxies.

ENCODE is also part of a trend that’s raising tough ancillary questions for scientists and science publishers. Though its principal investigators undoubtedly see the project as worthwhile, $185 million is a lot of money, and the reality of government-sponsored science is that it’s a zero-sum game. Despite what some big science proponents claim, funding for consortium-based “factory research” studies such as this necessarily comes at the expense of individual investigator-led projects. In an environment where thousands of promising young researchers are scrambling for grants, can we be sure this was the best way to spend those funds?

From the publishers’ perspective, big science is fraught with disputes over credit, concerns about oversight and data integrity, and fundamental questions regarding the proper length and format for a paper. It’s not even clear that a project like this should be published in a conventional journal; perhaps the data should simply go online, accompanied (or not) by a few comments from the lead scientists. As the ENCODE juggernaut keeps rolling along, and as subsequent, even bigger projects follow it, it might not even be possible to crank out papers for each new batch of work.

But this, too, is an expected result. This is what science does: uses what’s possible to redefine what’s possible. The ability to sequence a gene becomes the ability to sequence a genome becomes the ability to sequence a thousand genomes. When our minds can’t accomodate the new information, we’ll just have to expand them.

References:

1. Nature 489, 57–74 (06 September 2012) doi:10.1038/nature11247

2. Nature 489, 75–82 (06 September 2012) doi:10.1038/nature11232

3. Nature 489, 83–90 (06 September 2012) doi:10.1038/nature11212

4. Nature 489, 91–100 (06 September 2012) doi:10.1038/nature11245

5. Nature 489, 101–108 (06 September 2012) doi:10.1038/nature11233

6. Nature 489, 109–113 (06 September 2012) doi:10.1038/nature11279

Posted in Uncategorized | Tagged , , | 5 Comments

Stairway to Heaven

Posted on 2012.08.17 by Alan
Stairway to Heaven

Stairway to Heaven; North Philadelphia, November 2001.

Posted in Uncategorized | Tagged , , , | Comments Off