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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

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: derekb.lowe@gmail.com Twitter: Dereklowe

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December 2, 2010

Life With Arsenic: Who'd Have Thought?

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Posted by Derek

Update: a further look at the details of this paper is in a later post.

So: arsenic for phosphorus? That's the big news from NASA today. I listened to much of the press conference, and I've read the paper in Science. Is this real - and if it is, what does it tell us?

Let's do the second part first. Phosphorus is an extremely important element for every living thing on Earth. It's mostly found as phosphate, and phosphate groups are found all over the place: decorating proteins, carbohydrates, and lipids, as the invariable outside of DNA helices, and as the key part of the ultimate energy currency of every living cell, ATP. Phosphate's no bit player.

This is a good time to emphasize that (as far as we can tell) all life on Earth shares the same chemistry and the same kinds of biomolecules. Humans, frogs, fruit flies, fungi, tube worms on the ocean floor, lichens in Antarctica, and weirdo single-celled creatures living in boiling hot springs: we all have cells full of proteins, carbohydrates, lipids, and nucleic acids. We use DNA and RNA to pass on our genetic information, and the enzymes we use to manipulate them and to power our cells are all similar enough that we just have to share a common ancestor. (Either that, or life only gets going in a very specific way indeed).

One thought about today's press conference was that it might be announcing "alien life on Earth". That's been a subject of argument for quite a while. Even though everything we've ever found is of the same family tree, that doesn't rule out (logically or practically) the possibility that some other form of life, with different chemistry entirely, might be hanging out in its own environment. A good deal of searching has failed to turn it up, but (if it's such different stuff) we might be looking for it in the wrong ways, or might even have trouble recognizing it when we see it.

That's not what today's work has turned up, though - but it's probably the next best thing. What this group was looking for were hypothetical organisms that have learned to use arsenic instead of phosphorus. There are environments that are much richer in arsenic (and its corresponding arsenate salts) than they are in phosphorus. And arsenic is right under phosphorus in the periodic table, and forms similar sorts of compounds (albeit with rather different behavior), so. . .maybe it could substitute? Well, they didn't find any native arsenic-users - but they did force some into existence. They took a strain of bacteria from such an environment (Mono Lake sediments) and starved it of phosphate while providing it plenty of arsenate. The colonies that grew under these conditions were picked out and grown under even higher arsenate concentrations, and the process was continued stage after stage.

The end result appears to be bacteria that have incorporated arsenate into their metabolism. They still have phosphate in them, but not enough to keep everything running on a phosphate basis. Some parts have switched over to arsenate, without gumming up the works completely. That surprises me quite a bit - I really wouldn't have thought that things could be pushed that far. After all, in higher organisms, it's that arsenate-for-phosphate switch that's responsible for arsenic's reputation as a poison. Eventually, some key enzyme systems can't handle the switch and cease to function.

But not in these bacteria. They look different and grow more slowly than their phosphate-saturated brethren, and they'd clearly like ditch the arsenic at the first opportunity (add phosphate and they start growing more vigorously). But they're getting by, presumably with just enough phosphate to hold things together. (Have they hit the wall, one wonders?) A number of physical methods all point in the same direction, to arsenate being incorporated into their biomolecules. We still don't know where most of it goes, or how the various phosphate-manipulating enzymes manage to still work, but working out those details will keep a lot of people busy for quite a while. Personally, I'd love to see some X-ray structures of aresenate-containing proteins or nucleic acids, and I'm sure that the people who reported this are trying to get some.

So what does this mean? Well, you can apparently bend the most basic chemistry of life as we know it quite a bit before it breaks. As I said, I really would not have thought that this could be possible - we're all going to have to keep rather more open minds about what biochemical systems can handle. This makes the arsenic-from-the-ground-up idea look a lot more plausible, too, and you can be sure that the search for such organisms (using arsenate naturally, without having to be forced in the lab) will intensify.

It also makes you wonder about what other directions the biochemistry we know of can be stretched. Selenium for sulfur is my best guess - there, you have the advantage that selenium already has a small but real role in biochemistry as it is. I don't know of any environments that are higher in selenium than sulfur, but it would be worth trawling the closest candidates, culturing some bacteria, and giving them the same forcing treatment that was used here. If you really wanted to go wild, you could try pushing down to tellurium and down to antimony in the phosphorus column. Now, I really don't think those have much of a chance, but you never know. It's a lot more plausible to me than it was yesterday.

And the implications for extraterrestrial life are. . .what? Well, we keep finding the sorts of chemicals that we live with (amino acids, simple carbohydrates and the like) out in space. Our type of biochemistry might be fairly common - and if it is, it's good to know that it has a lot of wiggle room in it. It's hard for me to imagine a planet that's loaded down with arsenic and is short of phosphorus, but hey, it's a big universe. Big enough, it appears, for all kinds of weird things. It's great.

Comments (76) + TrackBacks (0) | Category: Life As We (Don't) Know It


COMMENTS

1. Joel on December 2, 2010 7:21 PM writes...

This is crazy! As a chemist who works with silicon, I often get asked about the theory of a silicon-based lifeform. But there's a whole ton of problems associated with that-- Si is less electronegative than H whereas C is more electronegative, which means nucleophilic attack will happen at the Si instead of the H, for example. There's lots of other reasons as well.

To think that AsO4- can behave similarly to PO4- in proteins and DNA, where the teeniest change in conformation means DNA is no longer a helix or you lose all enzyme activity, seems ludicrous. Ludicrous!

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2. Bored on December 2, 2010 7:22 PM writes...

My favorite original series Star Trek episode was called "The Devil in the Dark", and was about a silicon-based life form called a "Horta." It is in that episode that Spock exclaimed his now much-parodied "PAIN!!!" while mind-melding with the creature.

I remember reading somewhere that silicon-based life is highly unlikely. Maybe we assume too much sometimes. Like Derek points out, the Universe IS pretty big.

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3. Handles on December 2, 2010 7:44 PM writes...

I was taught that the trouble with silicon based life is the relative unimportance of p-p pi bonding for silicon, thus no silicon analogue of benzene, ethylene, CO2, ketones. SiO2 forms sand, not Si=O. Silicon based life would have to be almost unrecognisably different.

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4. R7 on December 2, 2010 7:50 PM writes...

What evidence do they have that arsenic really gets incorporated into biomolecules as opposed to those bacteria being ultra efficient with their phosphate or something? I understand they don't grow if there is neither phosphate nor arsenic, as that seems like the most basic control, but did they manage to isolate arsenic containing nucleic acids? (cannot access the article)

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5. Curious Wavefunction on December 2, 2010 8:20 PM writes...

Similar thoughts. It's worth remembering Frank Westheimer's "Why Nature Chose Phosphates" one more time. He would have been delighted.

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6. rhodium on December 2, 2010 8:37 PM writes...

Dewar had this wonderful paper in the first issue of Organometallics entitled "Why Life Exists". He pointed out that the reason SiCl4 is so much more reactive than CCl4 is not d orbitals, but just size. Its easier to pack five groups around silicon vs. carbon. Thus, room temperature silicon based life is problematic to say the least. John Edwards did some work that showed, likewise, the larger arsenate esters were about 10^5 faster at hydrolysis than the phosphates. Hence the surprise at today's results.
Given the near identity of biochemical reactions of phosphorothioates to phosphates (with the right chirality) I would have thought the first example of altered structural biochemistry would have shown up with an S for O substitution in DNA or ATP phosphates. Would an S for O substitution in arsenate esters affect hydrolysis rates very much? A quick SciFinder search did not turn up any data, perhaps its time to turn to the computer.

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7. Jose on December 2, 2010 8:52 PM writes...

How can the cellular machinery possibly function with such a massive switch? Staggering; Nobel Prize territory for sure!

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8. DoALLtheScience on December 2, 2010 10:07 PM writes...

I kinda think that NASA played up the hype way too much, as I don't think the general public will understand the weight behind this finding.

I remember when I first found out about hyperthermophiles, and the idea that something could grow at 100C really impressed me. I'm not saying it's the same thing, but somehow this arsenic utilizing bacteria isn't too much of a stretch for me to imagine.

Maybe this finding will remind us that different chemistry can leave different signatures, and the scope needs to be broadened if we hope to detect life elsewhere.

ps - longtime fan of your blog!

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9. gippgig on December 2, 2010 10:12 PM writes...

Silicon-based life would probably be electrical not chemical. Think photovoltaic cell and integrated circuit.

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10. Fbomber on December 2, 2010 10:16 PM writes...

I can't help recalling the diabolical four base codon-based cellular machinery a certain someone had engineered into e.coli a few years back. Not as cool as this study, but equally thought provoking.

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11. Curious Wavefunction on December 2, 2010 11:18 PM writes...

One thing that should be confirmed and re-confirmed beyond the slightest shade of doubt is that there is absolutely no phosphorus hanging around which would be sufficient to sustain core life processes; the entire conclusion depends on this fact. Traces of phosphorus could come from virtually anywhere. It's interesting to note that the phosphorus concentrations being measured are in femtograms, which means that the error bars need to be zealously monitored.

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12. gippgig on December 2, 2010 11:19 PM writes...

Way back in 1983 (PNAS 80 6303) researchers evolved a strain of B. subtilis that uses 4-fluorotryptophan instead of tryptophan (Also see Genetic Code Mutations: The Breaking of a Three Billion Year Invariance, PLOS One 5 e12206).
A strain of E. coli has been created that biosynthesizes p-aminophenylalanine & inserts it into proteins in response to the UAG codon (JACS 125 935).
If you define life as nontrivial self-replication, a living abstract mathematical pattern has recently been created (http://pentadecathlon.com/lifeNews/2010/05/oblique_life_spaceship_created.html).

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13. Arjun on December 2, 2010 11:28 PM writes...

I'm pretty sure I learned that bacteria grown in a selenium-rich environment will make their cysteines and methionines with selenium and go happily on their way, which would make this result not so surprising. Can anyone correct me?

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14. Anonymous on December 3, 2010 12:22 AM writes...

Perhaps they could use the reactome array to study the arsenate metabolism of this organism.

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15. CAprof on December 3, 2010 1:51 AM writes...

One of my friends over at the USGS tells me that the name of the strain of evolved bacteria (GFAJ-1) comes from the hopeful wish "Get Felisa a Job", as Felisa is the first author of the ms. Trite? Maybe. But it beats the heck out of some of the gene names assigned by the fly and worm crowd.

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16. lukas on December 3, 2010 2:14 AM writes...

@rhodium: IIRC, thioarsenates are unstable in non-alkaline media and will decompose to sulfur and arsenic(III) compounds.

This seems like it should be a problem generally for these organisms growing on arsenates in general: how do they avoid reduction to the highly toxic arsenic(III)?

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17. gippgig on December 3, 2010 3:22 AM writes...

Some bacteria have transporters that rapidly pump arsenite out of the cell. Their arsenate resistance mechanism is actually to reduce it to arsenite to get rid of it quickly. arsB/arsAB=transporter, arsC=reductase.

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18. lukas on December 3, 2010 3:59 AM writes...

Ah, I didn't know that, gippgig. Bacteria are weird.

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19. Anon on December 3, 2010 5:15 AM writes...

Just to confirm what CAProf's friends in the USGS are saying:
"Wolfe-Simon, a research fellow without a permanent university position, has jokingly named her new bacterium GFAJ-1. The initials stand for "Give Felisa a Job.""
http://www.aolnews.com/science/article/scientists-find-arsenic-eating-bug-that-holds-clues-to-extraterr/19740250

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20. Alekos60 on December 3, 2010 6:28 AM writes...

Relevant to all this discussion:
Studies have show that diets w/o Arsenic lead to retarded growth in chickens, rats, goats, and pigs.

Neilsen FH. Possible future implications of ultratrace elements in human health and disease. In Prasad AS,(ed). Trace Elements In Human Health and Disease, Vol 18, New York: Alan R Liss,1988:277-292.

But I cant find any description of As-related biological mechanism(s) in cells.

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21. Paul on December 3, 2010 7:29 AM writes...

@rhodium: IIRC, thioarsenates are unstable in non-alkaline media and will decompose to sulfur and arsenic(III) compounds.

These bacteria are from an alkaline lake (pH 10), but I don't know how alkaline their innards would be.

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22. alig on December 3, 2010 7:45 AM writes...

Bacteria don't have double-stranded DNA. I doubt this switch would be possible in any organism that did.

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23. R7 on December 3, 2010 7:58 AM writes...

Bacteria do have double-stranded DNA.

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24. alex on December 3, 2010 8:41 AM writes...

It is known (trace back to Meyerhof, 1934; Lagunas, 1968; C.-H. Wong 1989 also used vanadate)that instead of dihydroxyacetone-phosphate a mixture of dihydroxyacetone and inorganic arsenate shows similar substrate activity to fructose-1,6-diphosphate aldolase and glycerol phosphate dehydrogenase(key enzymes in glycolysis & gluconeogenesis)whereas dihydroxyacetone alone does not.

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25. lt on December 3, 2010 9:17 AM writes...

To quote the paper:

"The background PO4 3- in the medium was 3.1 (± 0.3) μM on average, with or without added AsO4 3-, coming from trace impurities in the major salts" but also

"It also grew faster and more extensively with the addition of 1.5mM PO4 3- (-As/+P, μmax of 0.86 day-1, Fig. 1A, B). However, when neither AsO4 3- nor PO4 3- was added, no growth was observed" and

"In +As/-P grown cells, the mean intracellular As was 0.19 (± 0.25) % by dry weight (Table 1), while the cells contained only 0.02 (± 0.01) % P by dry weight. This P was presumably scavenged from trace PO4 3- impurities in the reagents; and not likely due to carryover given our enrichment and isolation strategy [see above, (11)]. Moreover, when grown +As/-P this intracellular P is 30-fold less than our measured P values for this microbe when grown -As/+P (see above) and far below the 1-3% P by dry weight required to support growth in a typical heterotrophic bacterium (13)"

Pretty compelling but I can, for example, imagine the As and P being unequally distributed in cells so that perhaps only cells with a mostly P-linked DNA can replicatively competent.

The newly synthesized DNA strand would be mostly As-based and would result (after cell division) in one replicatively competent cell and one that cannot replicate itself but can still hang around as a cell-shaped little bioreactor. It would look like the cells are growing but actually only the original P-DNA bacteria would be making bunches of sterile copies of themselves. Or something...

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26. Slang4201 on December 3, 2010 9:30 AM writes...

A comedic take on it all: http://xkcd.com/829/

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27. ArsenicandOldLazy on December 3, 2010 9:30 AM writes...

Couldn't they have isolated the nuceotide fractions from several cells and simply assayed the genetic material itself for arsenic content?

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28. CYTIRPS on December 3, 2010 9:31 AM writes...

They have only shown that the bacteria are happy with As but they still need P. Furthermore, they have not determined any structure with the P/As substitution. The suggestion of P/As switch does not have solid proof. This paper would fail as an undergraduate thesis. It seems that someone is too eager to get on TV.

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29. CYTIRPS on December 3, 2010 9:32 AM writes...

They have only shown that the bacteria are happy with As but they still need P. Furthermore, they have not determined any structure with the P/As substitution. The suggestion of P/As switch does not have solid proof. This paper would fail as an undergraduate thesis. It seems that someone is too eager to get on TV.

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30. Andy Pierce on December 3, 2010 9:54 AM writes...

I also am skeptical. In particular I worry about the P they weren't able to eliminate due to alleged "trace impurities in the major salts". I also would have like to have seen direct evidence of As incorporation into macromolecular structures. Couldn't they have isolated DNA and run it through atomic absorption or similar?

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31. MIMD on December 3, 2010 10:01 AM writes...

There was a Star Trek episode where the alien (Horta) was a life form based on silicon, not carbon.

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32. Virgil on December 3, 2010 10:02 AM writes...

A wholesale swap of Selenium for Sulfur is quite unlikely, given the critical role of thiols in proteins (95% of proteins have at least one Cys), and the quite different preferred oxidation states of Cys vs. Selenocys. RSOnH and RSeOnH are quite different beasts. Given the increasing appreciation of the role of basic thiol redox chemistry in so much cell signaling, I would think that the only way Se could work as a replacement, would be in a vastly oxidizing environment (relative to the 21% O2 we're used to).

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33. MIMD on December 3, 2010 10:06 AM writes...

#31
oops, see that was mentioned already at #2. My bad.

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34. noname on December 3, 2010 10:36 AM writes...

C'mon folks, there is not enough skepticism here for a supposedly chemist-oriented blog. I'm looking at you Derek...

What was their arsenate source and how pure was it?
Did they try the arsenate medium selection experiment on bugs from the backyard rather than Mono Lake?
Why no direct measures on supposed arsenated biomolecules: no LC-coupled scintilation counting, no electrospray MS of DNA or nucleotides or arsenated proteins?

Wake me up when they have a mass spec of arsenated DNA. Outrageous claims require outrageous data.

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35. Curt F. on December 3, 2010 10:39 AM writes...

To Andy Pierce, Cytirps, ArsenicandOldLazy, and others who want "direct evidence of As incorporation into macromolecular structures":

Did you see Figure 2a in the paper??? I do not see how you can have read the paper, including Figure 2a and its caption, and still have the question that you have.

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36. luysii on December 3, 2010 10:53 AM writes...

There are more things in heaven and earth, Horatio, than are dreamt of in your philosophy

Shades of junk DNA

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37. Andy on December 3, 2010 10:55 AM writes...

I saw it, I just don't believe it. I'm in total agreement that outrageous claims require a much higher burden of proof. I don't think the authors have enough high-powered analytical chemistry.

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38. Algirdas on December 3, 2010 11:12 AM writes...

Virgil,

Selenium for sulfur in eukaryotes would likely be fatal, but bacteria are much simpler. Bacterial cytoplasm is reducing, what keeps cysteines in reduced sulfhydryl -SH state (as an aside, this makes it harder to produce disulfide-containing proteins recombinantly in E.coli; people resort to tricks like exporting expressed protein into periplasm, which is more oxidizing, or using specific strains of E.coli engineered to have more oxidizing cytoplasm ["Origami" from Novagen]). Presumably, seleno-cysteines should also stay reduced SeH , or ionized Se- due to lower pKa.

Protein X-ray crystallographers are fond of using Seleno-methionine labeled proteins, grown recombinantly in E.coli. But I think the only way they produce them is by growing methionine auxotroph E.coli and supplying Se-Met in the medium. All methionines are substituted with Se in entire cell, but of course cysteines and other metabolites retain sulfur. If one tried forcing Se instead of S in cysteines in bacteria, I would worry about inability to form "proper" coordination bonds in Zn-fingers and Fe-S clusters, as well as perturbations of redox equilibria. This will likely perturb TCA cycle and respiration, thus clobbering cellular energetics. Perhaps growing cells under anaerobic fermentation conditions has a chance? Would be fun.

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39. Curious Wavefunction on December 3, 2010 11:13 AM writes...

The concentrations of P they are talking about are woefully small; 9 femtograms. You would have to be very careful talking about such low concentrations. There's probably orders of magnitude as much P on the tip of my thumb. Again, they need to make absolutely sure that there are no traces of P coming from anywhere at all. Reminds me a little of 'transition metal-free' reactions which turned out to be catalyzed by transition metal traces.

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40. Zack on December 3, 2010 12:08 PM writes...

The authors identified the bacterium by sequencing its 16S rDNA. How did they do that? There is no way that arsenic based DNA is compatible with standard molecular biology.

Presumably the authors would say that they analyzed the DNA of the organism when it was grown on phosphorus, because then its DNA was made of phosphate. In fact they claim that the organism can use phosphate and arsenic interchangeably, and grow on media containing only one or the other.

In other words, this bacterium can make all of its biomolecules out of phosphate when grown on phosphorus containing media. When switched to arsenic, it makes all of its biomolecules out of arsenate. This means that all of the enzymes in this bacterium can handle both arsenic and phosphorus, despite their wildly different reactivities. That the elaborate mechanisms that this organism must have evolved to protect its arsenate metabolites from hydrolysis nonetheless do not interfere with it using phosphate chemistry for all the same molecules. Sure, that sounds plausible.

There is no way that this organism has arsenic in place of phosphate in all of its metabolites, including its DNA. The claim is just totally outlandish, and the authors haven't begun to establish the kind of proof necessary support it.

After the reactome array, I thought that Science had set a mark that would never be equaled for the publication of ridiculous chemistry in a prestigious journal. Apparently I was wrong.

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41. david on December 3, 2010 12:52 PM writes...

I don't buy it yet: Agree with the others that they will have to show that arsenate has replaced phosphate in FUNCTIONAL biomolecules (such as proteins or nucleic acids). Even if arsenate replaces some 1% of the phosphates it could mean that the cell still functions on mostly phosphate only biomolecules (the arsenate containing biomolecules (if they exist) might be either totally non-functional or have much lower "activity").
Way too much hype at this point...let's do some science first!

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42. azetidine on December 3, 2010 1:06 PM writes...

These guys are a bunch of C4H4AsH's.

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43. TAK on December 3, 2010 1:27 PM writes...

Recently in the Scientist (sorry, don't have the link), there was a story about bacteria living in very phosphorous poor areas. According to the article, there is a lake in Mexico that has such little phosphorous that some bacteria use alkyl sulfates instead of alkyl phosphates for some of their membrane lipids, though they still use ATP and phosphorous DNA. It was interesting to see that come out right before this paper hit the news wires.

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44. Curt F. on December 3, 2010 1:58 PM writes...

This paper may well have been overhyped, and NASA may well be guilty of excess PR.

The criticisms of the paper in this thread are so ridiculous that I have to wonder if people have read the paper, or just the press releases. The best way to defeat nonscientific hype that emerges from PR apparatuses of various funding organizations is to read the paper.

There is no way that this organism has arsenic in place of phosphate in all of its metabolites, including its DNA.

Where in the paper did the authors make that claim?

After the reactome array, I thought that Science had set a mark that would never be equaled for the publication of ridiculous chemistry in a prestigious journal. Apparently I was wrong.

The reactome paper has been found to be full of technical "errors", or, as some believe, fabrications. That paper has been retracted because of problems with the data. Are you alleging that severe technical errors will doom this paper to retraction? If so, the burden is on you to identify the errors.

I don't think the authors have enough high-powered analytical chemistry.

A nanoSIMS machine will set you back a few million dollars, ICP-MS ain't cheap either, and I would also call all the synchotron X-ray based analysis they did "high powered"...I agree, some HR ESI-MS of As-containing nucleotides, proteins, or metabolites would have been nice, and not having that data is a flaw in the paper. That said, just because the paper didn't use our favorite techniques doesn't mean its a fraud, it doesn't (necessarily) mean it didn't deserve to be in Science, and it definitely doesn't mean they didn't use "high powered" analysis.

Wake me up when they have a mass spec of arsenated DNA. Outrageous claims require outrageous data.

See my comments directly above, and see also Figure 2a, which is pretty close to being a mass spec of arsenated DNA. You are of course free to "wake up" whenever you want. Maybe when you do you will have more trenchant criticisms.

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45. Curt F. on December 3, 2010 2:04 PM writes...

By the way, here are my comments on the paper for anyone interested.

1. Their own data suggest that a maximum of 4% of intracellular P is in the genome, and that most of the radiolabeled arsenic goes into the protein/metabolite fraction, not into DNA. But then they fit their X-ray data for As in whole cells to a model of As incorporated into DNA. Shouldn't they fit it to a protein-As or metabolite-As complex instead?

2. Why is there so much arsenic in the -As/+P cells shown in Figure 2a? The ratio of arsenic to carbon (As:C) in genomic DNA from cells grown without arsenic is apparently only half of the As:C ratio in DNA from cells grown with arsenic.

3. Phosphorus limitation (w/ or w/o arsenic) is a well-known inducer of poly-hydroxybutyrate accumulation in many species. Not sure why they decided to speculate why PHB may be stabilizing arsenate esters.

4. There is a huge body of literature about arsenate and arsenite toxicity also being mediated by interactions with metabolite and protein thiol (~SH) groups. That could explain the spatial correlation of As with Zn and Fe that they observe by nanoSIMS (proteins, not DNA, usually have Zn and Fe).

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46. hn on December 3, 2010 2:12 PM writes...

Agree with Zack. I am entirely skeptical. I can't understand why it was published without more biomolecular characterization. What the heck is wrong with Science? The whole idea is so implausible. I would love to be wrong, but they need to do a LOT more work first.

Many people are going to look bad after this.

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47. Anonymous on December 3, 2010 2:14 PM writes...

From the abstract

Our data show evidence for arsenate in macromolecules that normally contain phosphate, most notably nucleic acids and proteins.

From the conclusion

We report the discovery of an unusual microbe, strain GFAJ-1, that exceptionally can vary the elemental composition of its basic biomolecules by substituting As for P.

From the body of the text

If AsO43- is fulfilling the biological role of PO43- then AsO43- should act in many analogous biochemical roles including DNA, protein phosphorylation, small molecular weight metabolites (e.g. arsenylated analogs of NADH, ATP, and intermediates like glucose and acetyl-CoA) and phospholipids.
Our data suggested that arsenic was present in a number of biomolecules and in particular we sought to confirm the presence of arsenic in the DNA fraction.


I'm sure that when the authors wrote these passages, what they were trying to imply was that there was only a minimal amount of arsenate in these organisms, and that the most of the biomolecules still required phosphate.

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48. Zack on December 3, 2010 3:09 PM writes...

Curt F.-

The authors claim that the organism can grow in media in which arsenic completely replaces phosphate. This implies either that: (1) arsenic will eventually replace phosphate in all of the organism's biomolecules, or (2) the organism does not have biomolecules. Take your pick.

As others have noted, the authors do not take seriously the possibility that the growth of this organism is due to phosphate contamination in their arsenic-only media. The authors observe this contamination but then dismiss it as unimportant.

As for the reactome array, I wrote here that the problem wasn't just that it was technically wrong or fraudulent. The problem was that the approach itself was illogical -- based on magical thinking about how enzymes work. Here, the claim is that a bacterium's proteome could, interchangeably, utilize exclusively phosphate or exclusively arsenate metabolites for its energy metabolism, genetic information and everything else. This is just as implausible -- in the absence of profound data explaining how this could work.

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49. Jim Hu on December 3, 2010 3:34 PM writes...

In the comments at PZ Myers post on this work, Rosie Redfield directs our attention to figure S2, which shows 75As:12C and 31P:12C ratios.

http://www.sciencemag.org/content/suppl/2010/12/01/science.1197258.DC1/Wolfe-Simon-SOM.pdf

In the media without phosphate the 75As:12C ratios range from about 2-4 x 10E-5. The 31P:12C ratios are 1-2 x 10E-3.

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50. Nyet on December 3, 2010 4:25 PM writes...

I think its time to start a betting pool. I believe the organism can absorb arsenic, and may have some limited use of it.

I don't buy the paper's broader assertions one bit.

HPLC/MS or MS-MS for the isolation of both the arsenic DNA and cofactor analogues should demonstrate the existence of arsenous nucleosides.
Since such analysis can be done on sub-nanomolar quantities, I hope the paper is holding back such info to get a maximum bang for its PR buck.

Two thumbs down.

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51. Curt F. on December 3, 2010 4:58 PM writes...

I don't buy the paper's broader assertions one bit.

What are the paper's "broader assumptions"?

The authors claim that the organism can grow in media in which arsenic completely replaces phosphate.

This is false, as a later passage in your own comment acknowledges. The key word rendering the sentence false is "completely".

I'm sure that when the authors wrote these passages, what they were trying to imply was that there was only a minimal amount of arsenate in these organisms, and that the most of the biomolecules still required phosphate.

I do not care to speculate as to what the authors were "trying to imply". I am interested in what they said. They acknowledged that there was still detectable P in cells grown in medium to which no P was intentionally added. At no point did they say that their bug had "completely" replaced "all" P for As.

I wonder if the differences in opinion the commentariat here have on this paper arise from differences in our underlying attitudes of what makes research publishable, and what makes it high impact. I believe that impressive thoroughness as well as scientific novelty and suprisingness both need to be considered, and further that a good deal of novelty and suprisingness can offset a lack of thoroughness. In my opinion, I think that's what's happened with this paper. Of course, the paper must be thorough enough that its conclusions follow from the data they have obtained. In my view, with this paper, it does: the evidence presented justifies, in my mind, the literal meaning of every sentence the authors wrote. Sure, it would be nice to have more data, especially HR ESI-MS data on some arsenated nucleotides, but even without that data, I can say that the discovery of a significant level of arsenic incorporation into biomolecules is (a) supported by their data, and (b) scientifically interesting.

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52. noname on December 3, 2010 5:04 PM writes...

@47 Anonymous:


I assume your last statement is tongue-in-cheek? Beacause that's exactly the opposite of how I interpret those statements.


@44 Curt F:

Gel + SIMS data just says there is As in the band. It doesn't say anything about the chemical environment of the As atoms. LCMS on the other hand, would nail that question. You should check out comment #45, from a guy who seems to have the same name (what a coincidence!). That guy "trenchantly" points out that the SIMS data actually shows a pretty underwhelming As enrichment in the +As/-P lane. I could tear that result apart with many different contamination arguments. But an LCMS of arsenated DNA would be rock-solid. I would bow down and declare obedience if that data was produced.


But Fig 2A is not nearly enough.

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53. jiri voller on December 3, 2010 5:34 PM writes...

If I were an extraordinary bacterium living in such a poisonous lake I would do everything to have higher levels of phoshate within the cytoplasm in order to prevent arsenate misincorporation. And if some mad scientist decided to starve me of phosphorus, I would secretly live off my polyphosphate stores.

If I were a mad scientist trying to make some
extraordinary bacterium to run on arsenate I would be monitoring the process by simply measuring ATP, because if there would be reasonable levels, something is wrong with the experiment (hypothesis).

I am always pleased by such primordial soup tales, but I do not believe in general P-As switch. You can possibly have heterogenous populations of biomolecules with a As fraction functional to some degree, maybe you can have some special case when As analogue works well (do they require As for optimal growth?) but nucleic acids definitely would not stand much As in the backbone.
On the other hand, trace incorporation of As nucleotides might lead to a higher mutation rate, which is always good when a population is not very happy...

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54. Anon3 on December 3, 2010 6:11 PM writes...

The experiments used in this paper are all indirect, lack clear statistical significance and do not address potential alternate explanations given the practical limitations of the techniques used.

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55. gippgig on December 3, 2010 10:21 PM writes...

#40: 16S rDNA sequencing can be done using PCR, which produces normal DNA even if the starting material isn't (as long as it isn't so exotic that it blocks the initial primer extension).

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56. DNA Chemist on December 4, 2010 1:02 AM writes...

They have only the most cursory evidence that arsenic is actually incorporated in DNA, and I am particularly skeptical of their use of EXAFS, but Curt F. is absolutely right: provocative and intriguing results should actually require a lower burden of proof for publication, because otherwise the important conversations never even begin. Their data clearly show that they have found an exceptional system, which stands a good chance of leading to decades of thrilling chemistry.

Also, for those demanding LC-MS, please remember that bacteria generate *genomic* DNA, not the nice 20-mers that we get off of a DNA synthesizer, and hence the experiment, while certainly important, is not quite as easy as you might think. For example, standard nucleases might not digest particularly well, and alkaline phosphatase is completely off the table!

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57. yonemoto on December 4, 2010 1:39 AM writes...

Damn MS it's such a horrible technique. What i want is a caesium chloride gradient - with ethidium bromide staining showing that the DNA is getting denser in the presence of arsenic. You gotta go old school on this kind of stuff. Who knows, maybe arsenic blocks the ability of whatever ionization method they have from correctly assessing the phosphate content in the medium.

Also, E coli growing totally in the presence of selenium instead of sulfur is known.

http://www.ncbi.nlm.nih.gov/pubmed/14604526

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58. gippgig on December 4, 2010 4:00 AM writes...

It is certainly possible to replace the deoxyribose phosphate backbone of DNA with something else - see peptide nucleic acids.
If this organism does substitute As for P it would not be necessary for its enzymes to work with both. It could have one set of enzymes that use P & a different set of enzymes for As. This sort of thing is common in bacteria. For example, in the absence of oxygen, many bacteria produce alternative "terminal oxidases" that, instead of using the hydrogen removed from glucose etc. to reduce oxygen to water, use it to reduce something else, such as sulfate to water and elemental sulfur.
Speaking of which, and this is pure speculation, one possibility is that this organism uses arsenate as a terminal oxidant, producing water and elemental or partially reduced As. Once it has reduced As, the bacterium may use it to make structural components (perhaps analogs of phosphonates rather than phosphates?).
What is really needed is to identify the chemical structures the As is in.

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59. Nicolas on December 4, 2010 4:35 PM writes...

Hi Derek, nice article. One suggestion about the website design. Make the column width shorter, on a widescreen monitor its hard to read the long lines. I know... I did resize my screen to about 800px but you should do it for me, Im the consumer here =)

Best Regards.

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60. mp on December 4, 2010 6:09 PM writes...

Thanks dawg!

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61. Kragen Javier Sitaker on December 4, 2010 7:00 PM writes...

It's a real joy to read such a high-quality comment thread. Thank you!

About "silicon-based" life, clearly silane backbones like ...-Si-Si-Si-... are far too unstable, at least anywhere near STP, but what about siloxanes? They're quite stable indeed, and you can make them arbitrarily complex without ever having to get near any carbon.

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62. ronathan richardson on December 4, 2010 8:40 PM writes...

I'm still skeptical, but I'm interested in the dire skeptics providing an explanation for the experiment in which the bacteria do not grow in no phosphate, no arsenic conditions, but then do grow when arsenic is added. Unless the arsenic they added contained a bunch of phosphate, which they tested and said it didn't, it seems pretty believable.

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63. Dddd on December 4, 2010 10:08 PM writes...

Thanks for your take on this subject, I find your style to be easy to understand and informative and wish people like you were the ones to cover scientific breakthroughs in the major news outlets.

Your knowledge and enthusiasm really shines through.

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64. Rockstar Sid on December 4, 2010 11:10 PM writes...

Who'd have thought this was possible? But I am sure 'they' will take years to go in depth into the Arsenic element.

Btw, very well written.

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65. Bankelal Chaurasiya on December 5, 2010 12:57 AM writes...

Bhai ji, thanks for this article. It's very informative and uses simple terms to make me understand the concept very well.

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66. kasper on December 5, 2010 6:15 AM writes...

@Joel: I think you've got things backwards. Carbon is more electronegative than hydrogen, thus nucleophiles attack the carbon. Should silicium replace carbon the nucleophiles would attack the hydrogen in stead of the silicium. Or maybe I'm misunderstanding you?

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67. Crubb on December 5, 2010 7:57 AM writes...

My science teacher refused to beleave my peanut was alive and now arsenic has been proven to be alive! He was rong and God knows he is rong

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68. Paul on December 5, 2010 10:25 AM writes...

Critical review of the paper: http://rrresearch.blogspot.com/2010/12/arsenic-associated-bacteria-nasas.html

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69. ROYAL HILL on December 5, 2010 3:32 PM writes...

WHILE ON A FISHING EXPEDITION WITH THE METALLURGY CLUB OF THE UNIV. OF ILL. IN CANADA NEAR THE MINNESOTA BORDER. WE CAME UPON A DEAD LAKE IN AN OTHERWISE TEEMING ENVIRONMENT. THE ONLY LIVING THING IN THIS 15 ACRE LAKE WAS SICKLY LOOKING GREY TO PINK KELP SHAPED PLANTS.I TOOK A SAMPLE OF THE SCHIST WHICH WAS COMPRISED THIS LAKES BOTTOM BACK TO THE UNIVERSITY AND FOUND VERY HIGH LEVELS OF ARSENIC. THIS MAY BE ANOTHER EXAMPLE OF ARSENIC SUBSTITUTING FOR PHOSPHORUS.

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70. Anonymous on December 5, 2010 3:57 PM writes...

The detailed critique by Rosie Redfield linked to in #71 is pretty devastating.

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72. Vader on December 6, 2010 11:38 AM writes...

I'm going to go way out on a limb, and predict that this will turn out to be the cold fusion of biochemistry.

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73. Curt F. on December 6, 2010 6:52 PM writes...

Thanks to the links to the webeasties and rrreasearch critiques of the paper. They are well-reasoned and make me more skeptical that this bug really has a large replacement of As for P in its DNA.

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74. Bored on December 6, 2010 10:03 PM writes...

Hey, I wonder if phosphorus makes a good "arsenic-based rat" rat poison?

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