Medicine! Poison! Arsenic! Life itself!

A few months back when the Nobel Prize for chemistry was announced, a few observers lamented that unlike physics and biology, perhaps chemistry does not have any 'big' questions to answer. So here's a question for these skeptics. What branch of science has the biggest bearing on the discovery of an organism that utilizes arsenic instead of phosphorus? If you say "biology" or "geology" you would be wrong. The essential explanation underlying today's headline about an arsenic-guzzling bacterium is at the chemical level. The real question to ask is about the key molecular mechanisms in which arsenic substitutes phosphorus. What molecular level events enable this novel organism to survive, metabolize and reproduce? Of course the discovery is significant for all kinds of scientists including biologists, geologists, astronomers and perhaps even philosophers, but the essential unraveling of the puzzle will undoubtedly be at the level of the molecule.

Many years back I read a classic paper by the late Harvard chemist Frank Westheimer called "Why Nature Chose Phosphates". In simple and elegant terms, Westheimer explained why arsenic cannot replace phosphorus and silicon cannot replace carbon in the basic chemistry of life. In a nutshell, phosphates have the right kind of acid-base behavior at physiological pH. The single negative charge in phosphates in DNA hinders nucleophilic attack by water and hydrolysis without making the system so stable that it loses its dynamic nature. Arsenates, simply put, are too unstable. So are silicates.

And yet we have an arsenate-metabolizing bacterium here. Arsenic, the same stuff that was used in outrageous amounts in Middle-Age medicines and which later turned into the diabolical murderer's patent weapon of choice makes a new appearance now as a sustainer of life. First of all let's be clear on what this is not. It's not an indication that "life arose twice", it does not suddenly promise penetrating insight into extraterrestrial life, it probably won't win its discoverers a Nobel Prize and in fact it's not even technically speaking an 'arsenic-based life form'. The bacteria were found in a highly saline and alkaline lake with a relatively high concentration of arsenic where they were happily using conventional phosphorus-based chemistry. The fun started when they were gradually exposed to increasing concentrations of arsenic and increasing dilutions of phosphorus. The hardy little creatures still continued to grow.

But the real surprise was when the cellular components were analyzed and found to contain a lot of arsenic and very little phosphorus, certainly too less to sustain the metabolic machinery of life. If true this is a significant discovery, although not too surprising. Chemistry deals with improbabilities, not impossibilities. Life forms utilizing arsenates were conjectured to exist for some time, but such total substitution of arsenic for phosphorus was not anticipated.

If validated the work raises fascinating questions, not about extraterrestrial life or even about life's origins, but more mundane and yet probing ones about the basic chemistry of life. I haven't read the original paper in detail yet, but here are a few thoughts whose confirmation would lead to new territory:

1. The best thing would be to get a crystal structure of arsenic-based DNA. That would be a slam dunk and would really catapult the discovery to the front ranks of novelty. The second-best thing would be to do experiments involving labeled phosphorus and arsenic, to find out the exact proportion of arsenic getting incorporated. Which brings us to the next point.

2. How much of the cellular components are trading phosphorus for arsenic? Life's molecules are crucially dependent on phosphate. Not just DNA but signaling molecules like kinases and AMP are phosphorus-based. And of course there's ATP. What is fascinating to ponder is whether all of these key molecules traded phosphorus for arsenic. Perhaps some of them like DNA are using arsenic while others keep on using phosphorus. Checking the numbers and concentrations left over would certainly help to decide this.

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 basic life processes; the entire conclusion depends on this fact. Traces of phosphorus can come from virtually anywhere; from the media (no, not the journalists, although it could come from them too), from human bodies, from laboratory equipment. A rough analogy from chemistry comes to mind; we have seen in the past how 'transition metal-free' reactions turned out to be catalyzed by traces of transition metals. If life is pushed to the brink by decreasing the phosphorus levels in its environment, the first thing we would expect it to do would not be to use arsenic but to scavenge the tiniest amounts of vital phosphorus from its environment with fanatic efficiency. 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. If it turns out that there is enough phosphorus to sustain a core cycle of essential processes while others are utilizing arsenic, the conclusions drawn would still be interesting but not as revolutionary as the current ones, and we probably won't be calling it an 'arsenic-based' life form then. In any case, my guess is that the utilization of phosphorus was selective and not ubiquitous. Organisms rarely utilize all-or-none principles and usually do their best under the circumstances.

If arsenic is truly substituting phosphorus in all these signaling, genetic and structural components, that would really be something because it would create more questions. By what pathways does arsenic enter these molecules? How does it affect the kinetics of reactions involving them? And most important are questions about molecular recognition. There are hundreds of proteins that recognize phosphorylated protein residues and similar other molecules. Do all these proteins recognize their arsenic containing counterparts? If so, is this the result of mutations in most of these proteins?; it seems hard to imagine that simultaneous mutations in so many biomolecules to make them recognize arsenic would result in viable living organisms. A more conservative explanation is that most of these molecules don't mutate but still recognize arsenic, albeit with different specificities and affinities that are nonetheless feasible for keeping life's engine chugging. The molecules of life are exquisitely specific but they are also flexible and amenable to changing circumstances. They have to be so.

3. And finally of course, how does the protein expression systems of the bacteria cope with arsenic-based DNA? As mentioned above, arsenates are unstable. To counter this instability does DNA expression simply get ramped up? How do proteins control the unpacking, packing, duplication and transcription of this unusual form of DNA? For starters, how does DNA polymerase zip together arsenated nucleotides for instance? How does the whole thing essentially hold together?

There are of course more questions. Whatever the implications, this is an interesting discovery that would keep scientists busy for a long time. Like all truly interesting scientific discoveries it asks more questions than it answers. But ultimately it should come as no surprise. The wonders of chemistry combined with those of Darwinian evolution have allowed life to conquer unbelievably diverse niches, from methane-riddled environments to hot springs to sub-zero temperatures. In one way this discovery would only add one more feather into the cap of a robust and abiding belief- that life is tough. It survives.

Selenium for sulfur should be next (but I wouldn't wait around for silicon...)

Update: Two first-rate rebuttals to the paper. One is an outstanding and meticulously detailed piece by University of British Columbia microbiologt Rosie Redfield. The other one is a Scienceblogs post. Basically the question keeps coming back to whether there could have enough phosphorus for survival. It's worth noting the application of Occam's Razor here. If bacteria which normally metabolize phosphorus were challenged with an arsenic-rich and phosphorus-poor environment, what would they first do? Start incorporating arsenic in their basic biochemistry or intensely adapt their life processes so that they zealously start sequestering and utilizing the smallest traces of the vital phosphorus? Occam's Razor and everything that we know about evolution suggests the latter.

Wolfe-Simon, F., Blum, J., Kulp, T., Gordon, G., Hoeft, S., Pett-Ridge, J., Stolz, J., Webb, S., Weber, P., Davies, P., Anbar, A., & Oremland, R. (2010). A Bacterium That Can Grow by Using Arsenic Instead of Phosphorus Science DOI: 10.1126/science.1197258