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Derek Lowe The 2002 Model

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Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: Twitter: Dereklowe

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June 1, 2011

Return of the Arsenic Bacterium

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Posted by Derek

You'll all remember the big news about the arsenic-using bacteria - that Science paper from last December. What you may not realize is that the paper is only now coming out in print. The delay seems to have been to allow time for an extraordinary number of responses to be published at the same time. I'll summarize those, and the counterarguments made by the original authors.

Rosie Redfield of UBC, whose blog was one of the earliest criticisms of the paper, objects that the culture media used were not pure. She maintains that there was enough phosphate in the growth medium to account for all the cell growth seen, without having to invoke arsenic-containing DNA. She also has a problem with the way that the DNA fractions in the original paper were (not) purified, pointing out that the procedures used could easily drag along many contaminants.

In response, Wolfe-Simon et al. don't find the trace-phosphorus objection compelling, they say, because the arsenic-stimulated organisms were grown under the same P background as the controls at that point, and the arsenic group grew much better. As for the DNA purification, they go over their procedures, state that they didn't see evidence of particulate contamination, and point out that negatively-charged arsenate is unlikely to stick to DNA unless it's covalently bound.

A team from CNRS and JPL makes the point (as others did at the time of first publication) that arsenic's own redox chemistry makes the original assertion hard to believe. Under all known physiological conditions, arsenate should be less stable than arsenite, and arsenite can't be a plausible substitute for phosphate (even if you buy that arsenate can). They also believe that the bacteria are running on residual phosphorus: "GFAJ-1 appears to do all it can to harvest P atoms from the medium while drowning in As. . ."

Wolfe-Simon et al. reply by saying that they specifically looked for reduced arsenic species in the cells, without success, and suggest that something must be stabilizing arsenate that no one has yet seen or considered.

Another team response, from Hungary and Johns Hopkins, objects to the way that the P:As ratios were calculated in the paper. The error for the dry-weight arsenic percentage in the bacteria is larger than the value itself, so you can't really be sure that there was no arsenic at all. The mass spec data used in the paper, they say, also have such high fluctuations as to make the numbers unable to support the paper's claims.

In response, Wolfe-Simon et al. say that they don't find the arsenic numbers to be all that variable, considering the conditions. And the phosphorus numbers don't vary much at all, by comparison, and the arsenic numbers are always higher.

Stefan Oehler, from Greece, asks why density gradient centrifugation of the supposed arsenic-containing DNA wasn't done (as did other observers when the paper came out). As-DNA should be heavier. Comparing hydrolysis rates of the As-DNA with the normal phosphate form "could also have been easily done", and he says that without these data, the paper is unconvincing. One major suggestion he has is to see how and where the bacteria incorporate radioactive arsenic.

David Borhani (ex-Abbott) has objections that are similar to some of the others. He's not convinced that the "-P" media really don't have enough phosphorus left in them to explain the results, and says that the agarose gels shown are hard to square with the paper's claims. (The phosphorus-containing DNA looks more degraded than the putative arsenic-containing sample, for example, and the DNA being compared is of different sizes to start with). He has the same problems with the error bars as mentioned above.

Steven Benner (who, interestingly, appeared at the original press conference back in December, albeit not as a cheerleader), comes at the problem from a chemical angle. The rate constants for arsenate hydrolysis gives you an expected half-life for such esters inside a cell of seconds to minutes (at best), which doesn't seem feasible for use in biomolecules. He goes over several possibilities for ways to make such linkages more stable - or for judging the literature on arsenate stability to be wrong - and can't make any of them work. Another big problem is that the phosphates in DNA have to survive as such for numerous steps in the cell, and it's hard to see how arsenate could substitute across such a wide range of biochemistry. He'd also like to see the As-DNA subjected to hydrolysis and to enzymes such as DNA kinase or exonuclease, to see how it behaves. "Above all", he says, do the radioactive arsenic experiment.

In response, Wolfe-Simon et al. say that there's very little data on the stability of arsenate esters of anything but very small molecules - steric hindrance, among other things, would be expected to make the bioesters more stable. They refer to a paper showing that arsenate esters of glucose were much more stable than expected, for example.

Patricia Foster of Indiana suggests that the process of raising the GFAJ-1 bacteria selected for mutants that have lost their phosphate inorganic transporter (Pit) system, but have pumped up their phosphate-specific transport (Pst) system. It's been shown in E. coli, she points out, that arsenate poisons the former transporter, but actually stimulates the latter, which would account for the apparent stimulatory effect of arsenic on GFAJ-1.

Wolfe-Simon et al. respond by saying that if the Pst pathway were stimulated, they'd expect to see evidence of arsenate detoxification pathways (thioarsenate, methylation, reduction), and they don't. (That seems weird to me - surely the organism, no matter what, is seeing a lot more arsenate than it can use, and would have to do some of these things?)

Finally, James Cotner and Edward Hall of Minnesota and Vienna, respectively, note that their own work was cited in the original paper on the phosphorus content of bacteria. They object, though, saying that their phosphorus-rich experiment make a poor comparison with the GFAJ-1 case. In fact, they say, they've now published a survey of the elemental content of freshwater bacteria, and that these can actually be highly depleted in phosphorus. The phosphorus content measured in GFAJ-1 does not, in fact, fall outside of the range seen in organisms grown under naturally P-limiting conditions.

Wolfe-Simon et al. reply that Cotner and Hall's numbers are taken from individual bacteria at the low end of the range, not whole populations, making them a poor comparison. Their whole-population values, they say, are actually similar to their own phosphorus control cultures, and are both higher than the arsenate-grown bacteria.

So, in the end, the authors are sticking to their original arsenic hypothesis. They agree that analyzing DNA after separating it from the gels would be a useful experiment (as Redfield and other propose), and they also say that they did not mean to suggest that the GFAJ-1 bacteria have a "wholesale" subsitution of arsenate for phosphate, just that they do have some. And they're making GFAJ-1 available to people who want to take a crack at their own experiments.

This is really a remarkable exchange, but mostly due to its sheer concentration in time and in publication. But this is exactly how science is done, although it usually happens a bit more slowly and in a more disorganized fashion than what we're seeing here. But these extraordinary claims have brought an extraordinary response.

I think that things have gone as far as they can with the data from the original paper, and it's fair to say that that's not far enough to convince a lot of people. Next step: more data, and more experiments. One way or another, this will get detangled.

Comments (35) + TrackBacks (0) | Category: General Scientific News


1. watcher on June 1, 2011 10:23 AM writes...

OK, the real test would be to see them form a company around this!

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2. RM on June 1, 2011 11:40 AM writes...

Quotes in a Nature News story questions how much independent verification we'll actually see, even with the bacteria being made available:

"If you extended the results to show there is no detectable arsenic, where could you publish that?"*


"I've got my own science to do."

*(One would naively hope that a refutation of a Science paper would warrant publication in Science, but we all know it doesn't always work that way; especially if you're using Conclusive Method Three, and Preliminary Methods One and Two have already been published by other groups.)

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3. AlchemistOrganique on June 1, 2011 11:48 AM writes...

Now, now...I'm sure we've all worked with people who are insidiously toxic enough to qualify as arsenic-based lifeforms. Yet another example of the breakdown in peer, I don't believe the conspiracy theory that the editors of Science let this crapfast get by in order to provoke active intellectual discussion.

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4. nitrosonium on June 1, 2011 11:57 AM writes...

has any outside group reproduced the claimed results?

i wish every experimental journal could be like Org. Synth.
submitted by:
checked by:

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5. NotAnAstrobiologist on June 1, 2011 12:17 PM writes...

The persistence of the author's views suggests that this may be a story that will never have an end.

Many of us have encountered difficulties in working with experimental systems, in which we have a large amount of confidence in (and we do get them to work...eventually). Proving that As incorporation is *never* happening will be a challenge, and bear little fruit to the person who allocates time and capital to that line of questioning.

Here are my predicted chain of events:

1)Someone repeats the experiments, and under stricter controls (more washing, purifying etc.) and does not observe any evidence of As incorporation in genomic DNA. Others will not be able to reproduce growth curves in the paper.

2)FWS team responds drags things out, tries to suggest that others are doing something wrong if they can't get the same result.

3)FWS team maintains that they believe (given the data in the original published paper) that there is As incorporation happening but at a very very low substitution rate.

4)The proposed substitution rate will be revised (multiple times) and whittled down to a number that is conveniently below the limit of detection for any feasible experiment.

5)The whole mess disappears in the sands of time without any admission of being wrong (just that their initial estimates of substitution rates were slightly higher than more refined observation methods suggest...all part of the process of science).

No one will ever be able to prove that there isn't a single As atom in the backbone of genomic DNA in some bacterial cell somewhere. This is the view that I think the authors will fixate on eventually.

Perhaps a touch cynical, but I chalk it up to the fact the people take cues that we see from a lot of public figures in the media: it is just never in your interest to smack yourself on the head and admit that you were wrong. Never.

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6. Hap on June 1, 2011 12:26 PM writes...

It's hard to believe that something is going to stabilize arsenate esters in DNA by 17 orders of magnitude without a counterexample to the small molecules that have been studied. You don't generally assume that an emergent phenomenon is present without evidence (or at least more direct evidence).

If arsenate were incorporated into the bacterium's DNA/RNA, there would probably have to be a lot of stabilizing moieties around (unless salt levels or solvent polarity or some medium effect could stabilize them instead), which would take a lot of effort for the cell - again, possible, but difficult.

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7. MoMo on June 1, 2011 1:07 PM writes...

I can't believe this paper has gotten this far and if the editors can't stop it then I will stop my subscription to Science due to this ridiculous mansucript.

The paper was written by astrobiologists with no regard to MODERN MOLECULAR BIOLOGY/BIOCHEMISTRY/INSTRUMENTAL ANALYSIS whatsover.

1. No incorporation of radiolabeled As studies.
2. No hint of mass changes in DNA/RNA via MS, although As isotopes abound.
3. Too much missing to spend time posting here.
4. Errors everywhere, as noted by the esteemed responders-but I was hoping to see a big-name microbiologist in there- to no avail.

Nothing here but words strung together by little-known astrobiologists studying extremophiles because they can't find a real alien.

But they are mistaken. The only thing alien is the first manuscript.
It is from another world.

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8. MoMo on June 1, 2011 1:34 PM writes...

One more comment. This is another example of how our tax-dollars are squandered by the Biological Elite. I see it everyday as the thousands of government workers dressed as students, professors and those that suck the life-blood out of real science get on the mass transit system in Boston to eke their existences.

I would start a tax-payer revolution against these frauds-if I wasnt busy doing real science.

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9. Andy on June 1, 2011 1:35 PM writes...

And, the $64k question: Will Felisa wind up getting a job?

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10. Mutant Dragon on June 1, 2011 2:23 PM writes...

Agree with @5. At this point, I think we can all agree this paper was flawed; unfortunately, getting Science and/or FWS to actually admit what we all really know is another question altogether. It's really tough to prove a negative, and it looks like FWS are just going to stick to their story, whether it makes sense or no.

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11. McFly on June 1, 2011 2:28 PM writes...

Cold Fusion, Marty! And yes, I built a time machine out of a DeLorean!

Ok, it was actually Mr. Fusion.

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12. Geo Guy on June 1, 2011 2:43 PM writes...

Astrobiology is the only science that has no data.

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13. Curious Wavefunction on June 1, 2011 3:26 PM writes...

I am a little afraid that this paper might end up in the twilight zone of published articles- neither proved nor disproved. That's slight worse than conclusive disproof.

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14. Anonym on June 1, 2011 3:49 PM writes...

From WSJ

Editors of the journal Science have asked the co-authors of a 2009 paper that linked chronic fatigue syndrome to a retrovirus called XMRV to voluntarily retract the paper.

But in written response Friday, study co-author Judy A. Mikovits of the Whittemore Peterson Institute for Neuro-Immune Disease said "it is premature to retract our paper." The letter was reviewed by the The Wall Street Journal.

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15. rocambolesq on June 1, 2011 8:27 PM writes...

In contrast to many of the respondents here, I think this is a wonderful example of how real science is thrashed out. It sounds like many here would have crushed Barry Marshall and his heresy of bacteria living in stomach acid, or Stanley Prusiner and prions, or Einstein and relativistic time and space, or Gerolamo Cardano with imaginary and complex numbers (centuries of controversy!). Everything is obvious in hindsight, but going forward, big leaps always entail some significant doubts and doubters. I agree with Derek that it's wonderful how Science has brought the innovators and their critics together for an open discussion. Yes, they have a lot of work to do to really demonstrate their finding, but there's not a lot of low hanging fruit in astrobiology!

Anyone see the news on another discovery suggestive for extraterrestrial life - tiny worms that appear to live miles below ground in 100 degree F, low oxygen environments? Life will take advantage of any niche it can find!

Subterranean worms from hell

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16. Jose on June 1, 2011 9:23 PM writes...

Never a good sign when the "responses to" outweigh the publication itself by 4-5x.

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17. Spiny Norman on June 2, 2011 12:45 AM writes...

"This is another example of how our tax-dollars are squandered by the Biological Elite."

There are EIGHT PUBLISHED CRITIQUES for this single paper, and probably several more that were suubmitted and not published.

Please, try just slightly harder to not be a retard.

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18. Steve Benner on June 2, 2011 1:14 AM writes...

You might want to read the "paper showing that arsenate esters of glucose were much more stable than expected." The reported half life for hydrolysis is two hours. Perhaps more stable than someone "expected", but still millions of fold less stable than needed to support genetics, or to appear as a band on a gel.

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19. MoMo on June 2, 2011 8:07 AM writes...

Whoa Spiny-Dude, I'll take the tard' remark just this once because I no doubt touched a nerve. But this Arsenic argument kills everyone's time, including the 8 responders, of which I am sure some are on government grants.

More power to them, but the tax-payer is footing the bill here and not getting a good ROI.

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20. Andy on June 2, 2011 8:29 AM writes...

More power to them, but the tax-payer is footing the bill here and not getting a good ROI.

Really? What do you think is the value of having people take a second look at the potential for As in therapeutics? So far this study hasn't really cost any money, certainly nothing like the cash poured down the GWAS rathole.

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21. MoMo on June 2, 2011 9:27 AM writes...

Arsenicals as potential therapeutics? Great idea if it wasn't already tried over 200 years ago. Tin is another good one to try too, and why not chromium while we are at it? Would be great for all those with ADHD and other neurological problems.

All of this has cost the taxpayer in man-hours billed to the American people, after all the Jet Propulsion Lab is paid for by us, isnt it?

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22. Andy on June 2, 2011 9:49 AM writes...

*giggle* Good thing there hasn't been any progress in HTS in the last 200 years right?

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23. Monte Davis on June 2, 2011 10:09 AM writes...

I don't believe the conspiracy theory that the editors of Science let this crapfest get by in order to provoke active intellectual discussion.

Roberto Goizueta, Coca-Cola CEO, when asked if the disastrous "New Coke" launch had been a clever ploy to get people talking about the company:

"we're not that smart, and we're not that dumb."

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24. MoMo on June 2, 2011 10:54 AM writes...

Progress in HTS? In the last 200 years? Judging by the state of the industry and the numbers of new drugs I would say NO.

But suggest to your company they screen arsenicals-let us know they treat you after that.

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25. bacillus on June 2, 2011 12:20 PM writes...

It would save considerable time and effort if the original team provided the DNA they believe contains incorporated As, rather than provide others with the bug and expect them to repeat all of the original experimental work that led to such fantastical molecules. This would also circumvent the argument that others failed to precisely replicate the necessary growth conditions.

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26. Feral Microbe on June 2, 2011 1:05 PM writes...

I'm running the same setup right now, only I'm using Old Lace. Keep you posted.

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27. JasonP on June 2, 2011 7:03 PM writes...

'Biological elite'? That's a new one. I've never once in my career felt elite, and in fact in the early 2000's would sort of resent the pay and influence of the arrogant, elite chemists. :)

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28. Anon on June 3, 2011 7:56 AM writes...

This whole debate reminds me very much of some work on the concept of "pathological science" as first enumerated by Irving Langmuir and elaborated on by Nick Turro at Columbia:

Regrettably, the story of As-containing bacteria seems to be meeting many of Langmuir's criteria of pathological science. I fear there is only one outcome here: the eventual disappearance of this notion into oblivion. It's irresponsible for a journal to publish these kinds of results when there are so many clear errors and omissions in the data package. The editors have let their desire to be on the bleeding edge get the better of them, to the detriment of the scientific community.

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29. Anonymous on June 3, 2011 9:39 AM writes...


In other words, it is possible to be so open-minded that your brain falls out.

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30. Nick K on June 3, 2011 11:50 AM writes...

Wolfe-Simon et al. could easily strengthen their case synthetically by coupling two nucleotides with arsenate or arsenite in place of phosphate as linker. If the resultant As-dinucleotide is reasonably stable in aqueous solution (which I very much doubt) then, and only then, will the rest of us take their hypothesis seriously.

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31. Anon on June 3, 2011 1:20 PM writes...

MoMo is right. Taxpayers pay for these experiments and the enormous amount of time it took to perform, write, and then defend this whole affair.

There should be a Senate investigation of NASA over their motives and reasons for publishing such data, especially when so incomplete.

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32. newnickname on June 3, 2011 4:21 PM writes...

I'm not buying the arsenic bacteria but ...

#21 MoMo: I think the argument stronger than therpeutic arsenicals is environmental remediation of arsenic pollution. Add these bacteria to an arsenic laden water supply, like Mono Lake, and they will consume all of the arsenic, leaving behind potable water, just like .. Mono .... Lake -- wait, I think there's a problem with that, too.

#30 Nick K: Not a good test, IMO. Cyclopentane-1,3-dione was thought to be incapable of a stable existence because so many attempts to make it had failed. "Yet when it appeared on the scene, ... it was produced by the action of boiling HCl and red phosphorus on a degradation product of aureomycin." (RB Woodward, Perspectives in Organic Chemistry, 1956.) Or beta-lactams, until Sheehan solved that in 1956 or so. I am willing to allow speculation that there may be a natural mechanism for formation of arsenic oligos and a natural stabilization system. The likely-to-be-unstable synthetic dimer doesn't fully address those bio-based possibilities.

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33. Anonymous BMS Researcher on June 4, 2011 11:23 AM writes...

I don't consider myself qualified to evaluate the technical issues with this paper, so on that my take is simply, "extraordinary claims (which these surely are) require extraordinary evidence."

One comment above mentioned Prusiner and prions. On that story I do feel qualified to comment. I read some of Prusiner's publications back in the 1980s when he was first making the claims, and was somewhat skeptical at that time. Since then a great deal more evidence has becom available, along with a much better understanding of protein misfolding as a mechanism involved in many neurodegenerative diseases. Today I do believe in prion, as do most researchers in the field. And even in the early years, Prusiner did a great deal more work charcterizing his discovery before publishing it than the "arsenic-eating bacteria" folks appear to have done.

Even now some experts still are skeprical about prions; when I was at Yale Medical School I met one of the most prominent critics of prions, whose views I believe still haven't changed.

My point is, Prusiner had a much more solid case for his remarkable ideas and still thet took a long time to gain acceptance.

And before somebody brings up McClintock's jumping genes, a friend of mine knew Barabara M. My friend says some popular accounts exaggerate the resistance in the field to the idea of jumping genes. The consensus early on was, "wild idea, if it was anybody else I would dismiss it out of hand, but if McClintock is making such a claim there must be something to it." The folks making the arsenic-eating bacteria claim don't have the kind of experience she had, which adds yet more to their burden of proof.

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34. Nick K on June 5, 2011 2:20 PM writes...

@32 Newnickname: Sorry, I don't follow your analogy with beta lactams and 1,3-cyclopentanedione. We know for a fact that polynucleotides held together by phosphates exist and are indefinitely stable in aqueous solution at neutral pH. Furthermore, we know that a phosphate in a strand of DNA enjoys no special protection against hydrolysis. I maintain that simply replacing phosphorus by arsenic in a dinucleotide would provide a good model for the putative As-DNA of Wolfe-Simon et al. Of course, as many people have commented, these authors should have obtained autoradiography evidence with radioactive As before publishing.

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35. MoMo on June 6, 2011 9:00 AM writes...

Nobody here has suggested that all new hypotheses need to be trashed-ala H. pylori hypothesis etc etc.

But if they had time and money to run X-ray synchrotron studies for X-ray analysis to solidify their studies, they should have backed it up with some other observations.

But that's what happen when you work for NASA. You are probably surrounded with robots and space gadgets and advanced alien spectroscopy like EXAFS. And its alot sexier than autoradiography any day!

Bring on a Senate hearing! This must piss-off a Republican out there somewhere!

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