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Corante Blogs examine, through the eyes of leading observers, analysts, thinkers, and doers, critical themes and memes in technology, business, law, science, and culture.

The Press Will Be Outsourced Before Stopped

Vin Crosbie, on the challenges, financial and otherwise, that newspaper publishers are facing: "The real problem, Mr. Newspaperman, isn't that your content isn't online or isn't online with multimedia. It's your content. Specifically, it's what you report, which stories you publish, and how you publish them to people, who, by the way, have very different individual interests. The problem is the content you're giving them, stupid; not the platform its on."
by Vin Crosbie in Rebuilding Media

Travels In Numerica Deserta

There's a problem in the drug industry that people have recognized for some years, but we're not that much closer to dealing with it than we were then. We keep coming up with these technologies and techniques which seem as if they might be able to help us with some of our nastiest problems - I'm talking about genomics in all its guises, and metabolic profiling, and naturally the various high-throughput screening platforms, and others. But whether these are helping or not (and opinions sure do vary), one thing that they all have in common is that they generate enormous heaps of data.
by Derek Lowe in In the Pipeline

Disrobing the Emperor: The online “user experience” isn't much of one

Now that the Web labor market is saturated and Web design a static profession, it's not surprising that 'user experience' designers and researchers who've spent their careers online are looking for new worlds to conquer. Some are returning to the “old media” as directors and producers. More are now doing offline consulting (service experience design, social policy design, exhibition design, and so on) under the 'user experience' aegis. They argue that the lessons they've learned on the Web can be applied to phenomena in the physical and social worlds. But there are enormous differences...
by Bob Jacobson in Total Experience

Second Life: What are the real numbers?

Clay Shirky, in deconstructing Second Life hype: "Second Life is heading towards two million users. Except it isn’t, really... I suspect Second Life is largely a 'Try Me' virus, where reports of a strange and wonderful new thing draw the masses to log in and try it, but whose ability to retain anything but a fraction of those users is limited. The pattern of a Try Me virus is a rapid spread of first time users, most of whom drop out quickly, with most of the dropouts becoming immune to later use."
by Clay Shirky in Many-to-Many

The democratisation of everything

Over the last few years we've seen old barriers to creativity coming down, one after the other. New technologies and services makes it trivial to publish text, whether by blog or by print-on-demand. Digital photography has democratised a previously expensive hobby. And we're seeing the barriers to movie-making crumble, with affordable high-quality cameras and video hosting provided by YouTube or Google Video and their ilk... Music making has long been easy for anyone to engage in, but technology has made high-quality recording possible without specialised equipment, and the internet has revolutionised distribution, drastically disintermediating the music industry... What's left? Software maybe? Or maybe not."
by Suw Charman in Strange Attractor

RNA Interference: Film at Eleven

Derek Lowe on the news that the Nobel Prize for medicine has gone to Craig Mello and Andrew Fire for their breakthrough work: "RNA interference is probably going to have a long climb before it starts curing many diseases, because many of those problems are even tougher than usual in its case. That doesn't take away from the discovery, though, any more than the complications of off-target effects take away from it when you talk about RNAi's research uses in cell culture. The fact that RNA interference is trickier than it first looked, in vivo or in vitro, is only to be expected. What breakthrough isn't?"
by Derek Lowe in In the Pipeline

PVP and the Honorable Enemy

Andrew Phelps: "Recently my WoW guild has been having a bit of a debate on the merits of Player-vs.-Player (PvP) within Azeroth. My personal opinion on this is that PvP has its merits, and can be incredible fun, but the system within WoW is horridly, horribly broken. It takes into account the concept of the battle, but battle without consequence, without emotive context, and most importantly, without honor..."

From later in the piece: "When I talk about this with people (thus far anyway) I typically get one of two responses, either 'yeah, right on!' or 'hey, it’s war, and war isn’t honorable – grow the hell up'. There is a lot to be said for that argument – but the problem is that war in the real historical world has very different constraints that are utterly absent from fantasized worlds..."
by Andrew Phelps in Got Game

Rats Rule, Right?

Derek Lowe: "So, you're developing a drug candidate. You've settled on what looks like a good compound - it has the activity you want in your mouse model of the disease, it's not too hard to make, and it's not toxic. Everything looks fine. Except. . .one slight problem. Although the compound has good blood levels in the mouse and in the dog, in rats it's terrible. For some reason, it just doesn't get up there. Probably some foul metabolic pathway peculiar to rats (whose innards are adapted, after all, for dealing with every kind of garbage that comes along). So, is this a problem?.."
by Derek Lowe in In the Pipeline

Really BAD customer experience at Albertsons Market

Bob Jacobson, on shopping at his local Albertsons supermarket where he had "one of the worst customer experiences" of his life: "Say what you will about the Safeway chain or the Birkenstock billionaires who charge through the roof for Whole Foods' organic fare, they know how to create shopping environments that create a more pleasurable experience, at its best (as at Whole Foods) quite enjoyable. Even the warehouses like Costco and its smaller counterpart, Smart & Final, do just fine: they have no pretentions, but neither do they dump virtual garbage on the consumer merely to create another trivial revenue stream, all for the sake of promotions in the marketing department..."
by Strange Attractor in Total Experience

The Guardian's "Comment is Free"

Kevin Anderson: "First off, I want to say that I really admire the ambition of the Guardian Unlimited’s Comment is Free. It is one of the boldest statements made by any media company that participation needs to be central to a radical revamp of traditional content strategies... It is, therfore, not hugely surprising to find that Comment is Free is having a few teething troubles..."
by Kevin Anderson in strange
In the Pipeline: Don't miss Derek Lowe's excellent commentary on drug discovery and the pharma industry in general at In the Pipeline

The Loom

« The Long, Long Sleep | Main | Book News, Part One »

November 14, 2005

Chronicle of a Death Foretold

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Posted by Carl Zimmer

This story starts in 1987, with the skin of a frog.

Michael Zasloff, a scientist then at NIH, was impressed by how well a frog in his lab recovered from an incision he had made in its skin during an experiment. He kept his frogs in a tank that must have been rife with bacteria that should have turned the incision into a deadly maw of infection. Zasloff wondered if something in the skin of the frog was blocking the bacteria. After months of searching, he found it. The frogs produced an antibiotic radically unlike the sort that doctors prescribed their patients.

Most antibiotics kill bacteria by jamming up their enzymes. The bacteria can no longer copy its DNA or expand its membrane as it grows or do some other task essential to their survival, and they die. Zasloff and his colleagues figured out that the antibiotics in frog skin worked entirely differently. These small molecules were attracted to the positive charge on the surface of many species of bacteria. Once they stuck to the membrane, the frog molecules changed shape, so that they punched a hole through the membrane. The bacteria's innards spilled out of the hole, leading to their death.

The antibiotics from frog skin proved to be just a tiny sampling of a huge natural pharmacy. Antimicrobial peptides, as these molecules are known, can be found in all manner of animals. We humans make a lot of them, both on our skin and in the lining of our guts and lungs. One reason that cystic fibrosis is so devastating seems to be that it monkeys with our ability to make antimicrobial peptides in our lungs. The microbes that swarm into the unprotected tissue cause the lungs to become inflamed, loading them with fluids. Many of the antimicrobial peptides found in one species are not produced by any other animal, and yet they are all remarkably lethal to bacteria.

Zasloff recognized a promising opportunity for inventing a new drug. The science of antibiotics hasn't moved forward much since the 1940s, when penicillin and other drugs were first introduced. These antibiotics, most of which were produced by fungi or bacteria, were miracle drugs at first. They can still clear up all sorts of infections in a manner of days--provided you're infected with a vulnerable strain of bacteria. Within a few years, every antibiotic that has been put on the market has triggered the evolution of resistance. Some bacteria acquire the ability to pump the drugs out, others to change the shape of their enzymes to make them harder to grab, and others do all sorts of other remarkable evolutionary tricks.

Before the antibiotic era, the mutations that help make bacteria resistant to drugs didn't bring a big benefit. In fact, they may have had nasty side-effects, slowing down the growth rate of microbes. As a result, they remained rare. But once bacteria began regularly to face these drugs, the evolutionary balance tipped. People often don't take enough antibiotics to wipe out their infections, allowing bacteria with a little resistance to survive and acquire new mutations. People sick with viruses regularly get antibiotics, even though the treatment is useless. Bacteria also encounter antibiotics in livestock, which get loaded with antibiotics to grow faster. Resistance genes can spread as microbes reproduce, and can get traded between different species. The situation has gotten so bad that scientists are now warning surgeons may soon be operating in conditions not seen since the Civil War, unable to stop bacteria that get into open wounds.

The secret of frog skin promised a solution to this disaster. A drug based on antimicrobial peptides might be able to wipe out bacteria that had evolved resistance to other drugs. And even more exciting was the possibility that these new antibiotics might be resistance-proof. Bacteria might theoretically able to evolve resistance to antimicrobial peptides by changing the charge on their surface so that the molecules wouldn't be attracted. But that wouldn't be just a tweak to an enzyme or some other series of small changes: it would be a fundamental alteration of the beast. Experiments seemed to back up this hunch. Some scientists tried to produce resistant bacteria by randomly mutating their genes and then seeing whether any mutants could survive a dose of antimicrobial peptides. No luck.

But a Canadian evolutionary biologist named Graham Bell suspected that bacteria--and their evolutionary potential--might be more powerful than others thought. Michael Zasloff for one didn't think so. But as a good scientist, he was willing to put his hypothesis to the test. Remarkably, it failed.

The researchers began by exposing bacteria to low levels of antimicrobial peptides. They would then use a few of the survivors to start a new colony and then expose the bacteria to slightly higher levels of the poison. As they report in the Proceedings of the Royal Society of London, 30 out of 32 colonies evolved to be resistant to a full does of antimicrobial peptides. It took only about 600 generations for them to do the impossible.

The new paper doesn't offer any evidence for what the evolved bacteria are doing to escape antimicrobial peptides. It is hard to pinpoint mutations that produce new traits, and even harder to figure out exactly how they change the workings of a microbe. So we may have to wait to learn the trick that bacteria have discovered. But the results are enough to raise serious concerns about the future of antimicrobial peptides. People who take full doses of the drugs might wipe out all the bacteria infecting them, but microbes that are exposed to low levels--in people who don't take full prescriptions, in animals, or even in the environment--could evolve resistance. As the bacteria became stronger, they would be able withstand higher doses. They might gradually invade a new ecological niche: the world of full-strength antimicrobial peptides.

The new research shows yet again that it's pointless to rely on personal incredulity to understand the workings of evolution, despite what some creationists may claim. But it also reveals a paradox: if resistance can emerge so easily, why are bacteria susceptible to antimicrobial peptides in nature? Clues to the answer lie in the evolutionary history of the peptides themselves. Scientists have compared peptides to figure out how they evolved from common ancestors. The peptides have been evolving at high speed for millions of years. Ancient genes were accidentally duplicated, and mutated so that they produced molecules with different structures. But different parts of the genes evolved at different rates. Each gene for an antimicrobial peptide contains a signal sequence that acts like a mailing label: once the DNA code of the gene is translated into a protein, the signal sequence tells a cell where the protein should go. The signal sequence in antimicrobial peptides barely changes over hundreds of millions of years--presumably because all of these molecules need to go to the same place, out of the cell. But the portion of the gene that codes the bacteria-fighting end of the protein has changed drastically over time. In fact, some research even suggests that this part of the gene is more prone to mutating than typical DNA.

This pattern suggests that antimicrobial peptides are effective only if they are continually reinvented. When a population of frogs begins to colonize a new habitat, for example, they may encounter new microbes. Their old antimicrobial peptides may not be very effective against these pathogens, but they can rapidly evolve new ones. But even if animals stay put, they may evolve new peptides. That's because pathogens can evolve the ability to knock out these weapons. Certain bacteria, for example, can produce enzymes that neutralize antimicrobial peptides. Hosts that can evolve new peptides that can't be knocked out so easily may be more likely to survive. And so the arms race continues.

There's another lesson for the drug industry in the evolution of these molecules. Not only have animals repeatedly experimented with new versions, but they never rely on just one. Each species may produce ten different kinds of antimicrobial peptides, and the molecules are often most effective in combination (for reasons scientists don't yet understand). By using a range of different peptides at once, animals may thwart the evolution of resistance, because bacteria never get intensely exposed to a single drug.

It would be absurd to model man-made antimicrobial peptides too closely on natural ones. After all, natural selection produces remarkable antibiotics only through the different levels of success of different genes. Some animals die, in other words, and some don't. But it does offer some guidance. Just because microbes can evolve resistance to antimicrobial peptides doesn't necessarily mean they will if these drugs enter the marketplace. If doctors use them sparingly, combine several kinds of antimicrobial peptides, and continue to invest in new versions (like this extremely powerful one from a mushroom reported by Zasloff in October), they may be able to stay one step ahead of the bacteria. We just need to face evolution with our eyes open.

Update: link to Bell and Zasloff paper fixed, I hope.

Comments (4) + TrackBacks (0) | Category: Evolution


COMMENTS

1. John Timmer on November 16, 2005 11:15 AM writes...

I tried to follow the link to the Royal Society journal article, and came up with an article on bears:
The dilemma of female mate selection in the brown bear, a species with sexually selected infanticide

The correct link appears to be:
http://www.journals.royalsoc.ac.uk/(cit1f1nr53gezqqct20s5jn5)/app/home/contribution.asp?referrer=parent&backto=searcharticlesresults,1,1;

Permalink to Comment

2. Cayte on November 17, 2005 07:14 PM writes...

All I could access was the abstract. It wasn't clear from the abstract whether Graham Bell used a single peptide or the whole cocktail. But analog implied a single peptide to me.
The claim for natural antibiotics that I've heard is that they delay resistance because they are a mix so the germs have to jump over the whole gauntlet instead of a single hurdle.

Permalink to Comment

3. Gabriel G. Perron on January 10, 2006 07:25 PM writes...

In response to Cayte...

We have used a single peptide in this experiment because we wanted to test the evolution of resistance in bacterial cultures faced to one peptide. First, because it has been claimed that resistance would not evolve due to the biochemistry of bacterial cell membrane (Zasloff 2002). Second, because as explained by Carl Zimmer the commercial use of peptides or antimicrobials creates ideal conditions for the evolution of resistance: the disproportionate concentrations of the peptide in the environment increases selective pressures for resistance to that one favored antimicrobial and dilutes the beneficial effect of natural RAMPs cocktails.
Remember that although Sir Fleming foresaw the evolution of resistance to conventional antibiotics, the scientific community was convinced that resistance would be very unlikely if not impossible… an example strikingly very similar to the current (hopefully past!) thinking on RAMPs.

Permalink to Comment

4. Gabriel G. Perron on January 10, 2006 07:27 PM writes...

In response to Cayte...

We have used a single peptide in this experiment because we wanted to test the evolution of resistance in bacterial cultures faced to one peptide. First, because it has been claimed that resistance would not evolve due to the biochemistry of bacterial cell membrane (Zasloff 2002). Second, because as explained by Carl Zimmer the commercial use of peptides or antimicrobials creates ideal conditions for the evolution of resistance: the disproportionate concentrations of the peptide in the environment increases selective pressures for resistance to that one favored antimicrobial and dilutes the beneficial effect of natural RAMPs cocktails.
Remember that although Sir Fleming foresaw the evolution of resistance to conventional antibiotics, the scientific community was convinced that resistance would be very unlikely if not impossible… an example strikingly very similar to the current (hopefully past!) thinking on RAMPs.

Permalink to Comment

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