How a college student can derive the RNA world hypothesis from scratch

One of the greatest breakthroughs in twentieth century biology was the finding that RNA can serve as a catalyst and drive some of life's essential chemical reactions. This discovery which garnered a Nobel Prize led the way to understanding ribozymes, splicing and the structure and function of the ribosome. It also propelled the conception of the so-called "RNA world hypothesis" for the origin of life which suggests that RNA was the earliest enzyme. This hypothesis in various forms has since been regarded as the single most plausible hypothesis for the origin of life.

The purpose of this post would be to postulate that, as stunning and important as the RNA world hypothesis is, it probably could be derived by a smart (admittedly a really smart) high-school or college student with no more than a basic understanding of organic chemistry, molecular biology and evolution. This exercise is in no way meant to be a put-down of the significance or difficulty of this discovery; on the contrary it drives home the beautiful simplicity and logical nature of the hypothesis.

Let's start with a fundamental question which a precocious college student might ask. "Why, if RNA is so unstable, does it serve as the genetic material at all?". This question actually encapsulates the entire essence of the RNA world hypothesis. The instability of RNA is obvious from its chemical structure- RNA has two hydroxyl groups at the 2' and 3' positions on its ribose sugar. The problem is that the 2' OH can serve as an internal nucleophile and break a 3' phosphodiester bond as illustrated at the top of this post; in fact that's precisely the reaction that RNA catalyzes in a ribozyme. The reaction is usually helped along by magnesium ions.

Thus, phosphodiester linkages in RNA are (relatively) quite unstable. DNA- deoxyribose as the name indicates- lacks the 2' OH group and is therefore more stable. This makes it clear why RNA cannot serve as the original genetic material (DNA) but only as the messenger; the fidelity of information storage and transfer by the original genetic material is of such paramount importance that RNA would simply be too unstable to do the job. Evolution could entrust only DNA with the core function of being the blueprint of life.

So far so good, and a fine argument for why DNA and not RNA is the genetic storage disk. But then the question arises; why use RNA at all? The question is highlighted even more by the fact that while DNA functions in the nucleus, RNA transfers to the cytoplasm and performs the key function of protein synthesis. From a chemical standpoint, the cytoplasm is a much more hostile place than the nucleus, with several oxidizing, proteolytic and other kinds of enzymes waiting to chew up biomolecules. Entrusting the translation of genetic information in such a destructive environment to an unstable molecule like RNA sounds dangerously irresponsible of evolution.

But wait! The very instability of RNA that denies it the coveted function of the original genetic material also confers on it a marvelous capability of towering significance- catalytic ability. But why would you even think of catalysis in the first place? Well, the essence of evolution is the careful weighing of tradeoffs. If RNA is too unstable as the genetic material, it likely has some other property which compensates for this apparently deal-killing instability. At this point our intrepid college freshman will have to scratch her head and remember a few basics of enzyme catalysis. A little contemplation leads to the entirely reasonable hypothesis that enzyme catalysis needs at least two catalytic groups. Even if this hypothesis is wrong, it is still certainly true that two catalytic groups are better than one, and we have to remember than evolution is a greedy miser which can hungrily seize on any incremental advantage, no matter how small. Think of any kind of enzyme catalyzed reaction involving electron flow, say, the cleavage of peptide bonds by proteases. At the very least, you need one nucleophilic group to attack the peptide bond and another group (a positively charged one) to stabilize the resulting concentration of negative charge.

With this reasoning in hand, it is not too difficult for our admirable student to arrive at two great truths. Truth no. 1: In RNA, there are two hydroxyl groups. Truth no. 2: these groups are right next to each other. This is a really big deal. Our knowledge of enzymes tells us that proximity can greatly enhance reaction rate, sometimes by several orders of magnitude. This final capstone on the chain of thinking finally leads our precocious young adventurer to compile a succinct set of steps for arriving at the RNA world hypothesis through armchair speculation:

1. DNA is the original genetic material because RNA would have been too unstable. But then why does RNA exist at all?

2. The essence of evolution is tradeoffs. Perhaps RNA could have served another very important function that could have compensated for its instability?

3. One of the key steps in the origin of life was the capacity for chemical catalysis. Enzymatic reactions probably need at least two catalytic groups in close proximity to each other.

4. RNA with its two hydroxyl groups right next to each other could possibly function as a catalyst, in stark contrast to DNA which has only a single such group. This slight but all-important structural difference would have compensated for losses incurred due to instability and would have led RNA to transcend a barrier that was of superlative importance to the origin of life- the ability to bring about chemical reactions. QED.

Of course, the fundamental psychological barrier would still have been to think of something other than proteins acting as an enzyme. But this barrier is probably not as hard to surpass as we think. A hundred years before anything was known about the RNA world, giant chemical industries were already using metal-based catalysts to speed up reactions of great economic importance- the Haber-Bosch process being only one of many. If lowly metals could bring about such a diverse variety of reactions, then it's not a long stretch to think of simple molecules unrelated to proteins doing the same.

There have been a handful of transformations that have been responsible for the ascendancy of life on this planet. The tiny modification that added a single hydroxyl group to RNA would probably rank at the very top. Rephrasing Robert Frost, two roads diverged in a wood, and I took the one with the 2' hydroxyl group.

Our precocious youngster goes peacefully to sleep that night. She dreams of life on an RNA world.

Note on the cultish status of organic synthesis: Part 2

In 1828, Friedrich Wöhler synthesized urea - a substance hitherto thought to be produced only by living organisms - from simple inorganic substances. The discovery was a watershed in the history of science. In one fell swoop it shattered the widespread doctrine of vitalism which held that there is something fundamentally different between the animate and inanimate worlds. Wöhler was the triumphant messenger, heralding great expectations for the new adventurers while shattering the dreams of keepers of the faith.

Only ten years before in 1818, a different kind of vitalism was being conceived. That was the year when Mary Shelley published "Frankenstein; or, The Modern Prometheus". "Frankenstein" did for the science fiction genre what Wöhler did for chemistry. It infused the vivid imaginations of generations of writers, thinkers and movie-makers with notions of reanimating dead matter.

Now fast-forward to 1960. Woodward synthesizes chlorophyll. Chlorophyll. The substance which more than any other fuels life on this planet. There are telling similarities between Wöhler's synthesis of urea, Shelley's creation of "Frankenstein" and Woodward's synthesis of chlorophyll. All three speak to man's mastery over Nature. All three embody a conscious or unconscious sense of hubris. And all of them tell us that the allure of vitalism is still alive, albeit in a very different sense. The chemists of Wöhler's generation strove to annihilate the distinction between living and non-living. But the synthetic chemists of Woodward's generation want to do one better and are closer to the brilliant, troubled protagonist of Shelley's novel; they want to not only starkly state the difference between life and death but they want to become the creators of both.

Wöhler's urea and Woodward's chlorophyll demonstrate the second reason for the cultish status of organic synthesis. The first was the cult of personality, but the second is the all-powerful cult of elemental ambition. There is a truly seductive feeling of power in being able to synthesize a substance like chlorophyll whose constitution and very identity seemed for years to be among Nature's most closely guarded secrets. A creature who could unravel the workings of this most fundamental of nature's engines would announce himself to be a true master of creation. What better way to make this announcement than to not only tease apart the strands of this secret but to create it from scratch? In fact it's worth noting the other landmark Nobel Prize winning discovery related to photosynthesis: the unraveling of the structure of the photosynthetic reaction center protein by Harmut Michel, Johann Diesenhofer and Robert Huber. As important as it was, the psychological impact of even this discovery cannot compare to the creation of chlorophyll through human ingenuity.

That is why, among all the chemical sciences, organic synthesis still enjoys a unique status. It harkens back to one of man's deepest and most primitive desires, to remake the world in his image; to first closely study, then mimic, and finally improve over nature. There can be no higher accolade for a species than to be congratulated for being able to trump it's very creator. This accolade is manifest in the Nobel committee's tribute to Woodward as well as to organic synthesis when it noted that "It is sometimes said that organic synthesis is at the same time an exact science and a fine art. Here Nature is the uncontested master, but I dare say that the prize-winner of this year, Professor Woodward, is a good second." In addition organic synthesis not only creates the molecules of life but it saves life, and the production of novel drugs further drives the image of synthesis as an instrument of human triumph.

The new science of synthetic biology promises to satisfy the same craving. The deliberate synthesis and rearrangement of genes to create new organisms from scratch promises the same kind of psychological benefits that the total synthesis of complex substances afforded to both organic chemists and lay audiences. No wonder that discoveries by Craig Venter and others are heralded in the press as the dawn of a new age, and they undoubtedly are. But in terms of their goals, these spectacular advances simply constitute the extensions of an age that began in 1828. And the psychological need goes back even further, when man was living in caves and creating innovative tools, agricultural implements and clothing from animal hides.

It's just vitalism and Frankenstein writ large all over again.

The long grave dug?

Every time there is any kind of nuclear incident, the media does a hit job on nuclear power. People who support nuclear power and try to put things in the right context become "pro-nuclear partisans". The New York Times's reporting during the aftermath of the tsunami has been appalling. Not all the reporting was bad, but coverage of the tens of thousands of deaths from the tsunami and earthquake was relegated to the side-lines while alarmist headlines about the nuclear accident were splashed on the front page every day. Plus the paper did a masterful job of pitching contradictory facts. For a long time it stuck with the line that the accident was comparable to Chernobyl. It certainly was serious, but there was absolutely no evidence for the comparison, nor was there any discussion of the fundamentally flawed design of the Chernobyl reactor in comparison to the Fukushima reactor which stood up admirably to a 8.9 magnitude earthquake followed by a gigantic tsunami.

Then two days back, The Times blithely flashed the confusing headline that the Japanese have "upgraded" the level of the accident to Three Mile Island levels. This made it sound like the disaster was now considered worse than before, which was in complete contravention of the facts and a masterful piece of obfuscation. The fact that the Japanese considered the accident to be milder than TMI before makes the Times's constant comparison to Chernobyl absurd and shamefully alarmist. While The Times is no longer trotting out the line about Chernobyl, it has not made any sustained effort to educate the public about the completely benign nature of TMI in terms of the consequences. In addition the paper had another confusing headline yesterday titled "Radiation Plume Reaches U.S., but Is Said to Pose No Risk". As Rosie Redfield notes on her blog, the studied ambiguity in the statement (someone says the plume poses no risk, but we won't say that explicitly) does nothing to put the risk in the right context.

The New Yorker is no less biased. In the most recent issue there are two pieces on nuclear energy. One is a moderate critique by the environmentalist Elizabeth Kolbert while the other is a rather extreme and emotional critique by Japanese writer Kenzaburo Oe. While Kolbert does not go overboard, she casually throws around some opinions about how nuclear reactors are not protected against terrorist attacks. This is in spite of the fact that American nuclear power plants are well-secured, terrorists would have a very hard time stealing nuclear material from a power plant even if they overwhelm security, they would have a hard time getting away unnoticed, and the stolen nuclear material would be extremely dangerous to handle and capricious in its behavior in a weapon. Of course all this just ignores the fact that terrorists are so much more likely to smuggle in a weapon from abroad than they are to foolishly attack a US nuclear reactor for making one. Kolbert also has biased critiques of lack of evacuation plans for people around a nuclear reactor (ignoring accident probability, radius of evacuation and the amount of radiation released) and spent fuel storage (no discussion of reprocessing, quotes from the Union of Concerned Scientists which has long-since vigorously opposed nuclear power).

Oe is worse; adopting one of the oldest tricks in the anti-nuclear playbook, he makes no attempts to separate nuclear weapons from nuclear power and constantly conflates the two ("Lessons of Hiroshima"). Basically there is no balancing pro-nuclear perspective. The New Yorker should be ashamed of itself for this one-sided reporting.

All this is keeping in line with physicist Bernard Cohen's extensive writings. Cohen has been a tireless and rational promoter of nuclear power for more than three decades and his articles and books are thoroughly readable. If you don't have time for his books, you should definitely at least read his essay in a recent collection of essays expounding on the relationship between science and politics (Politicizing Science, 2003). Cohen analyzed various accidents and their coverage in the New York Times in the 70s (even before TMI). He found that while there was a clear correlation between the number of deaths and the subsequent coverage for all other kinds of accidents (low number of deaths corresponding with low coverage), when it came to nuclear accidents the Times went ballistic. The coverage was all out of proportion with the number of deaths- zero. That's exactly what's happening right now. In addition Cohen recounts several instances of being routinely ignored and even reprimanded when he wrote letters to journalists whose coverage of nuclear power contained numerous factual (not literary) mistakes. Even trying to correct the science brought forth responses like "I don't tell you how to do research so you don't tell me how to do journalism". As Cohen sums it up:

"To attack the nuclear power industry, activists needed ammunition, and it was readily found. They only had to go through the nuclear power risk analysis literature and pick out some of the imagined accident scenarios with the number of deaths expected from them. Of course, they ignored the very tiny probabilities of occurrence attached to these scenarios, and they never considered the fact that alternate technologies were causing far more deaths. Quoting from the published scientific analyses gave the environmentalists credibility and even made them seem like technical experts."

The situation seems to be no better right now. Needless to say this distortion of the truth is not just appalling but it could be a certain recipe for disaster even as nuclear power needs to be a healthy component of the mix for combating climate change. Liberals always like to complain about how the conservative media distorts and cherry-picks the science on global warming. The litmus test of the liberal media's scientific integrity would be its coverage of nuclear power. Sadly it seems to have already failed this test multiple times.

A hundred years from now when we are possibly writing the epitaph for the human race, I wonder if one of the turning points on the road to perdition would be seen to be our inability to rationally balance the benefits and risks of the greatest source of energy that mankind has discovered.

Gray and Labinger on chemistry's big problems

The irrepressible Harry Gray and his colleague Jay Labinger have an editorial in Science. The editorial asks some of the questions that we here and others have asked about chemistry; does chemistry have any "big questions" akin to physics and biology that would make it attractive to the public? The editorial is a little short on detail but the authors rightly propose that there are indeed a few big questions in chemistry but they are not as easily visible and sometimes seem to be couched in the veil of biology and physics. As an example of a "big question", the authors cite the cracking of the photosynthesis puzzle that involves both intimately understanding the process and duplicating it in the laboratory.

"We suggest that the noble themes in chemistry are there, but may be a little harder to see. One can look outward to the universe, or inward to the mind, and recognize the complexity and profundity of the questions to be answered. The problems that contemporary chemistry tackles are just as fundamental, but may not be as immediately obvious to the non-chemist. We could illustrate this claim in many ways, but perhaps one has received the broadest sustained attention: photosynthesis. How can light be harvested and converted to electrochemical energy that is sent off so efficiently in two directions: to both reductively generate the building blocks of life from carbon dioxide and oxidize water to oxygen? This extraordinarily complex question, to be sure, is closely linked to aspects of both physics (but cannot be completely reduced to physics) and biology; but the answer clearly lies in the realm of chemistry. And the workings of each individual component, as well as the entire integrated system that nature has constructed, pose questions that are fully as deep and inspirational as those in any other field of science. Moreover, on the practical side, the answers will be needed to devise methods for making comparably effective use of solar power, which at present appears to be the only resource of sufficient magnitude to cope with the world’s long-term energy needs."

Photosynthesis is indeed a hard, rewarding unsolved problem but I am disappointed that the authors did not instead pick the origin of life as the one shining chemical puzzle of all time. If you really had to pick one problem that's as important as the truly big problems in cosmology or biology, you would pick the origin of life. It is of enduring value to working chemists and it is easier to pitch to the public as a profound philosophical conundrum compared to photosynthesis. And the origin of life has the additional advantage that unlike photosynthesis, it probably cannot be solved even in principle, adding to the mystery and the everlasting allure.

What is chemistry's greatest achievement?

In a recent post Chembark asked what the greatest achievement of chemistry in the last 20 or 30 years was. I would like to expand a bit on my comment on that post.

The way I think about it, the greatest achievement of chemistry in the last fifty years or so is not any particular discovery but a validated philosophy; that given the time, funds and motivation, we can make virtually any molecule or material by the application of rational physicochemical principles. Of course we are still far from designing functionality on demand (it's much easier to make structures), and pure rationality in designing molecules is still a fond hope since most rational design of molecules like drugs is what I call "rational in retrospect". But what we have is still a substantial achievement.

We can make this question even more general. What is the greatest (or perhaps the top three greatest) achievement of chemistry since it emerged from the darkness of alchemy? Comments are welcome and there are many choices. Lavoisier's enumeration of the differences between elements and compounds, Dalton's atomic theory, Wohler's synthesis of urea, Mendelev's periodic table, Gibbs's application of thermodynamics to chemistry, Staudinger's unveiling of the nature of polymers and Pauling's application of quantum mechanics are all worthy candidates. But I would venture that none of these single achievements was as important as the development of a general philosophy of chemistry; that by the application of principles grounded in other disciplines like physics combined with carefully tabulated empirical knowledge about the properties of substances, one can crack open the mysteries of the structure of matter and use this hard-earned knowledge to synthesize new materials never seen before. It was the coming of age of the precise yet usefully capricious mix of rigor and empiricism that defined and continues to define modern chemistry.

Indeed, one can broaden the question to include other disciplines and even all of science. What single achievement was the greatest in all of physics? I would say it was the discovery that relationships between properties of objects can be precisely quantified by proportionality. Biology? The meticulous, exhaustive classification of species and creatures combined with the knowledge of the workings of those creatures at the molecular level.

And so it goes for science itself. What was the greatest discovery in all of science? Some may say it was Newton's laws of motion, or Einstein's theory of relativity, or quantum theory, or Darwin's evolution by natural selection, or Maxwell's laws or those of thermodynamics. But while these discoveries are undoubtedly paramount, they miss what is the most important contribution of science to the world. This contribution was the well-defined process of hypothesis testing and experimentation and formulation of theories that allows us to divine new truths from nature. The process is messier than it looks on paper but it has still served as a most rewarding guide. It has allowed science to make the modern world in its image.

The greatest discovery is not an island but a whole continent of ideas.

Perspective...again

No one advocated halting the manufacture of methyl isocyanate or shutting down the chemical industry after the Bhopal tragedy of 1984 which killed thousands more than any nuclear accident. The Gulf oil spill also did not provoke howls to terminate oil production. And of course, you don't hear calls for permanent evacuation of coastal communities because of the occasional tsunami that can wipe out these cities in a catastrophe much worse than a nuclear engineer's worst nightmare.

I cannot add much to what's being already said and I join millions in wishing the unfortunate citizens of Japan the very best. But even a serious accident like the one currently unfolding at the Japanese nuclear plant should not blind us to the bigger picture. Predictably, there have already been calls from alarmists to stop all nuclear building in the US. In keeping with the media's appetite for sensationalism, the Washington Post put an adequately fear-invoking and alarmist photo on their cover page. As others have noted, we don't regularly hear calls to halt oil and natural gas production after accidents that are much more damaging in terms of environmental destruction and human life compared to the one or two serious nuclear accidents we have witnessed. The only response after a crisis such as the present one should be to put together a review of reactor safety in other parts of the world and how it could possibly be improved to withstand such freak scenarios as the ones we are witnessing. But when presented with an unfortunate, unlikely case, human nature is to throw out the baby with the bath water.

Already people are comparing the current crisis to Chernobyl. This is a ridiculous comparison, partly because the current reactor and the contingency response have been much better than the ones during Chernobyl and partly because if you really want to cite the worst case scenario, you might as well hold up the Hindenberg as an argument against air travel. In case of Chernobyl the accident was of course the result of a combination of several factors, including a fundamentally flawed design and human inertia engendered by communist ideology that prevented rapid response. The number of deaths from Chernobyl cannot be known with certainty, but it's certainly less than deaths from any number of other industry-related accidents. One can be almost sure that the effects of the present accident are going to be far less severe because of more open communication and prompt response. In fact it's heartening that these reactors with 50-year old designs did relatively well in spite of being struck by one of the biggest earthquakes in recorded history. With modern designs where passive systems can cool the core in spite of loss of electrical power, one can be much more confident about containment of radiation (as an aside, I wonder why the seawater that was pumped into the Japanese reactor did not contain cadmium chloride for neutron absorption).

Here's one of the things the US should do. Just like they did after Chernobyl, top scientists in this country should put together a committee after the facts of the Japanese disaster become known. They should undertake a review of all the nuclear reactors in the US and write a report detailing their safety features as well as possible measures that can be included in the unlikely case of natural disasters like the one in Japan. There should be two versions of this objective, apolitical report. One version should be more technical and comprehensive and can serve as a blueprint for future action. The other version should explain the committee's conclusions in simple terms that can be understood by the public and by members of Congress. Finally, and this is key, this version should be publicized as widely as possible in an effort to educate the public about the true risks and benefits.

Ultimately the life and death of a technology is not decided by how harmful or beneficial its effects are but by simple economic tradeoffs. Automobiles and fossil fuels have killed hundreds of thousands, but nobody advocates their extinction simply because their benefits are perceived to greatly exceed their costs. A similar argument can be made for knives and guns. On the other hand, nuclear power which boasts an impeccable safety record compared to the chemical and fossil fuel industry still sets off alarm bells and brings forth calls for its demise. This is partly because of the irrational psychological gut reaction that people still associate with the words "radiation", "nuclear" and "meltdown" (an unfortunate consequence of the fact that the world's first exposure to nuclear energy was by way of nuclear weapons) but more importantly because of the simple fact that nuclear is not seen as an indispensable energy option even now.

What will it take for the situation to change? Perhaps when war in the Middle East decimates dependence on fossil fuels or when extreme climate change exacerbates our lifestyles to an unacceptable extent, we will finally accept nuclear energy as an energy-intensive, climate change-friendly power source whose risks must be evaluated and managed just like those of others. The only question is whether it would be too late then.

Important or interesting; what is more important?

In the last decade or so I have sat through my fair share of talks and interviews by Nobel laureates and other famous scientists. Typically when students in the audience ask these men and women what formula they should follow for making great discoveries, the usual answer is that there is no one formula, but if anything, people who want to do science at the cutting edge should work on important problems. One of the practical reasons for this piece of advice is that science being a generally difficult endeavor, you are probably going to spend a lot of time on both unimportant and important problems, so you might as well tackle the important ones.

I think the point is well-taken but its value has also been exaggerated. First of all, in science, you don't always know what's important. You may think that neuroscience is the hottest field of this century but you still don't know exactly what lines of research would lead to important discoveries in it. However, my greater objection to this constant emphasis on importance is that it detracts from what really drives scientists- the fact that scientific problems are interesting. We do science not because it may lead to some important discoveries or even a greater understanding of the universe (which it inevitably does) but because scientific conundrums tickle our brains cells like no other, they excite our imagination, the logic inherent in them sparks our curiosity and fuels our hunger to know more. The real driving force of science, in Richard Feynman's words, is the pleasure of finding things out. These things may or may not turn out to be important, but what really matters is whether they are interesting.

Sure, keeping the big picture in mind and not doing derivative work does make sense. But sometimes even relatively trivial problems can be interesting in their own right and an obsessive focus on importance may lead us to simply ignore more modest problems even if they are very interesting. Examples of such problems can be found in any scientific journal. Pick up the latest issue of even a top journal like JACS and you would be hard-pressed to judge the true importance of 90% of the papers. Is the latest discussion of entropy in drug binding, intricacies of solar cell design or the most recent breakthrough in organocatalysis going to truly lead to something important? Who knows. But what we do know is that at least some of them are interesting; maybe the organocatalysis reaction has an interesting mechanism, maybe the drug binding displays entropy-enthalpy compensation, maybe the solar cell material exhibits an unusual crystal structure. Most importantly, all these things are not just interesting but they are fun to discover.

The last word again belongs to Feynman. After the war, when he was a young assistant professor at Cornell, Feynman thought that he had burnt out, that the war had sapped his best years and that he had nothing left to contribute to science. Then one day during lunch in the cafeteria, he watched someone throw a dinner plate up for fun. The thing wobbled and Feynman noticed that there was an interesting relationship between motion at the edge of the plate and its center. Intrigued, he spent the next few hours working out the relationship from first principles. He went to the great physicist Hans Bethe's office and showed him the calculation. Bethe asked him what the importance of the observation was. Feynman cheerfully told Bethe that the calculation had no importance whatsoever, he just had such a bloody good time doing it.

That's the main reason why all those Nobel prize winners also did science and what they should emphasize more. And that's why we should do it too. Not because someone someday may use what we do - although that is a laudable goal- but because finding out how the world works delivers such a neat little intellectual kick to our mental apparatus. Interesting is just so much more important than important.

Book review: Andrew Roberts's "The Storm of War"

The contemporary World War II historian faces a monumental task. He must sort through the enormous literature on the most devastating conflict in human history, both known and recently unearthed, and then pick out the gems. He must then string these gems together into a coherent narrative that strikes the right balance between offering all important details and yet not miring the reader in a dense thicket of minutiae. The achievement of this objective is the mark of a true historian, and in his new, stunningly succinct and yet comprehensive history of World War II, Andrew Roberts more than accomplishes this objective and reveals himself as a historian of the first rank; in the words of The Economist, "Britain's finest military historian".

What distinguishes Roberts's book from other World War II histories is that it's simply the most stunning encapsulation of every single front in the conflict in a relatively slim 600 pages that I have read. In his drive to leave no stone unturned and his capacity to compose brief portraits of key people and events, Roberts surpasses even eminent historian John Keegan. Roberts's style is distinguished by terse, tightly knit chapters that deliver the goods in brief paragraphs and analyses. While generally chronological and covering each important front, the chapters also include separate ones on the Holocaust and on strategic bombing. A single, absolutely masterful chapter summarizes the conflict at the end. Bringing new information to bear on well-known events, Roberts provides striking new insights into the war and puts some long-harbored beliefs to rest.

The most important thread running through Robert's retelling of The War constitutes the singular mistakes that Adolf Hitler made and his underlying motivations while also highlighting his strengths. Hitler had an unusually prodigious knowledge of military equipment and detail and was a shrewd controller of men; a striking example was when, in the aftermath of his victory over France, he suddenly promoted twelve generals to Field Marshals, thus generally diluting the distinguished character of the rank and emphasizing his dominion over his officers. However, whatever his strengths were were far overshadowed by the stupendous mistakes he made. Admittedly the greatest was to decide to attack the Soviet Union. Hitler completely underestimated the sheer tenacity of the ordinary Russian soldier and citizen and, on the other side of the continent, also underestimated the tenacity of that tiny island named England. His second great mistake was to foolishly declare war on the United States. Here Hitler made an even more elementary error in underestimating the enormous resources and production capacity of the United States which soon started bolstering the great Soviet war machine as well as the British. Most importantly, Hitler committed both mistakes fueled by his essential Nazism and thirst for Lebensraum (living space) in the East. And the fundamental underlying ideology driving this thinking which finally drove a stake into his grand plans was his racial theory about inferior Slavs and Jews. It was this rabid racial ideology for instance which prevented him from shrewdly taking advantage of Eastern Russians' contempt for Stalin's regime and turning them into allies; instead Hitler assigned the feared Einsatzgruppen to essentially wipe out Russian towns from the map. These SS units participated in the wholesale personalized murder of a million Russians in 1941 alone, killing on a scale whose sheer personal nature and horrifying brutality dwarfs even the later industrialized gassings of The Holocaust. Roberts does a superb job of highlighting how it was this basic racial and xenophobic mentality that drove almost all of Hitler's mistakes including most of his military ones.

Roberts also has revealing analyses of more tactical errors by Hitler. These include not ramping up U-boat production in time to possibly starve Britain and make her sue for peace, not focusing on fighter development without which his cherished bombers would be useless, and being almost blissfully indifferent to the Japanese whose help he could have considered in invading the Soviet Union. And then there were of course his two cardinal tactical errors; letting the British get away at Dunkirk (Roberts demolishes the belief that Hitler did this because he was interested in peace negotiations with Britain) and even more importantly, halting the advance on Moscow in the summer of 1941 and suddenly driving his forces to the South. This miscalculation, combined with Stalingrad and the later great tank battle of Kursk, signaled the death knell for the Nazi regime.

Roberts also pays due attention to the Pacific theater of war including the incredibly bloody fighting at Guadalcanal, Iwo Jima and Okinawa (although readers wanting a more complete treatment should check out Max Hastings's excellent "Retribution: The Battle for Japan, 1944-1945"). His discussion of this front includes a superb chapter on the Battle of Midway which was the turning point in the Pacific war, and most notably a detailed and riveting analysis of the more under-appreciated stage of the battle in Burma. The British response in Burma against a determined enemy in a sweltering thicket of tropical heat and rain forests was comparable to anything else in the War, and Roberts calls the defeat of the Japanese in Burma the "greatest gift that the British could have given India". He also has detailed and tactically accomplished accounts of the war in North Africa, (against Rommel's famed Afrika Corps), Normandy, Sicily and Italy and of the Ardennes offensive (The Battle of the Bulge) and the march towards Berlin. These accounts are interspersed with sharp portraits of men like FDR, Churchill, Eisenhower, Montgomery, Manstein, Rommel, Keitel and Goring.

Robert's chapter on the U-boat war is particularly skilled and he carefully documents the initial disasters that befell the British navy in the Atlantic. The U-boats sank millions of tons of shipping, and if Hitler had stepped up production earlier he could have starved off Britain much sooner in the war. However, in the end it was not the resilience of the Royal Navy nor Germany's increasingly dwindling war production capability that were decisive; it was a secret weapon that was developed by mathematician Alan Turing and his colleagues at Bletchley Park near London. It is difficult to overemphasize the absolutely crucial role that breaking the Enigma code of the Nazis played in the war. It is a silent undercurrent running through Roberts's narrative but its overwhelming importance is clear; it was code-breaking that won the critical Battle of Midway, and it was code-breaking that proved pivotal not just in the U-boat battle but in North Africa and in Normandy. It was not the atomic bomb, not even radar, but the obscure code-breaking work of brilliant scientists toiling away in the utmost secrecy that really won the war.

Further on Roberts has separate chapters on the Holocaust and on strategic bombing. His chapter on the Holocaust is painful to read and captures the key facts, including why FDR avoided bombing the train tracks to Auschwitz; there was genuine concern about killing prisoners (concern that in hindsight seems misguided) and such bombing was seen as a diversion of bombers from German cities. Roberts's analysis of strategic bombing is highly readable. Along with the atomic bombing of Japan, it's strategic bombing that is the most controversial part of the Allied campaign. The destruction of Hamburg and Dresden are well known (the latter made famous by Kurt Vonnegut's "Slaughterhouse Five"). Roberts wisely avoids passing any moral judgement and simply analyzes whether the carpet bombing of German cities worked, and whether it was necessary. The answer to the first question is decidedly yes. There is a clear correlation between dwindling German war production and air power and the Allied bombing campaign; the bombing also kept German aircraft away from the Eastern front. The answer to the second question is more ambiguous, but in hindsight provided by the first answer it too appears favourable. Certainly the number of people killed in German cities by bombing, while quite high, was dwarfed by ground losses on both Western and Eastern fronts.

If I have a minor gripe with the book, it is that Roberts could have added about a hundred more pages and fleshed out the chapters on Stalingrad and the Holocaust in more detail. No matter how many books you read about the War, the Eastern Front and the Holocaust comprise a set of events which constantly beggar belief by their sheer magnitudes and leave one's mind shatteringly numbed. While 6 million Jews and others were murdered in an orgiastic frenzy of factory-like slaughter, 27 million Russians lost their lives in what can only be described as Dante's worst nightmare, a sea of blood whose volume is unmatched in human history. Just one statistic puts the staggering Russian losses in perspective; for every American soldier who died on the battlefield, 60 Russian soldiers lost their lives. About a million men died at Stalingrad alone compared to half a million or so American soldiers in the entire War. At the same time, the unimaginable ferocity on the Eastern Front was possibly matched only by Josef Stalin's own monstrous barbarity toward his own people; not even Hitler personally tortured and murdered hundreds of thousands of his own officers and generals for absolutely no reason. In the annals of twentieth century brutality nobody can match the excesses of Stalin, and these excesses manifested themselves dangerously in the complete lack of preparation the Soviet Union faced during the early Nazi onslaught. It was only the gargantuan resolve of ordinary Russian citizens and soldiers combined with the certain death at the hands of their own officers that deserters would face (thanks to Stalin) that forced every Russian to fight for his or her life. The Nazi-Soviet conflict can only be seen through the lens of one of those mythical conflicts signaling the end of the world. While tomes have been published both on this conflict as well as the singular horror that was the Holocaust, Roberts has relatively brief (although highly well-informed) chapters on both topics and I thought that an addition of a hundred or so pages would have been a small sacrifice for some added narrative on these earth-shattering events.

But these are minor issues. In the purview of his analyses, the crisp and riveting style of his narrative and the comprehensive detailing of every single important front, battle and fact of this great conflict, Roberts is second to none. While Roberts's basic thrust is to highlight Hitler's tactical mistakes, his overweening racial ideology and his conflict with his generals, in retrospect of course such analysis is relatively easily enunciated. Just think of how we would have written history differently had the Nazis, God forbid, won the war. We would possibly be talking about French casualties incurred by Allied bombing instead of British casualties in the Blitz (the former actually exceeded the latter), and General Mark Clark letting the Nazi tenth army get away in Italy instead of Hitler letting the British get away at Dunkirk. Given the capacity of Hitler's armies, the experience and fighting capability of the German solider (probably the most well trained of any in the conflict), the superiority of German weaponry and the brilliance of his generals (of whom some like Manstein, Rommel and Guderin were regarded as the finest strategic minds on any side), it was by no means obvious that the Nazis would lose. But as Roberts's overall message in the book overwhelmingly indicates, in the end Adolf Hitler lost the war because of the same reason that he almost won it; because he was a Nazi.

I highly recommend this sweeping historical narrative. The Second World War was a transformative event in human history that should be remembered until the end of time. It deserves the constant and passionate attention of the finest historians of their generations, and Andrew Roberts proves himself as one of the best of this class.

Why should chemists study the origin of life?

In the past we have alluded to the fact that the origin of life (OOL) is a quintessentially chemical problem. But from a professional standpoint, what's in it for chemists and why should they care? Some thoughts:

1. OOL is the ultimate interdisciplinary playing field: No matter what kind of chemist you are, OOL provides an opportunity for you to flex your intellectual muscles. Organic chemists can of course contribute directly to OOL research by speculating on and studying the kinds of reactions that would have been important in molecular origins. Some reactions such as the Strecker reaction (for amino acid synthesis) and the formose reaction (for carbohydrate synthesis) have already been proposed as the frontrunners for the genesis of life's molecules. Both reactions have been around for decades, but it was only recently that the concrete connection to OOL was made. What other reactions in the organic chemist's bag of tricks are applicable to OOL? The question should tickle organic chemists' brain cells like no other.

Other kinds of chemists also have a lot of potential contributions to make. The connection to biochemistry is obvious; for instance, how did the crucial watershed event of membrane formation come about and how did the earliest enzymes form? Inorganic chemists have made new inroads into OOL research, especially through pioneering research implicating metal sulfides in deep sea hydrothermal vents as precursors to organic life and inorganic surfaces (such as clays) as templates for primitive evolution and polymerization. Analytical chemists can bring their impressive phalanx of instrumentation like mass spectrometry and chromatography to bear on the problem. And theoretical and computational chemists can contribute to OOL by performing calculations on the forces operating in the processes of self-assembly that must have been key during the early moments of molecular organization. Of course, none of these areas is insular and every problem stated above demands the attention of every conceivable kind of chemist. Thus, there is a slice of pie in OOL for every chemist who dares to dream and the field guarantees an unlimited number of interdisciplinary collaborations.

2. OOL is a proving ground for basic chemical concepts: Just like organic synthesis is supposed to provide the ultimate training laboratory for fundamentals like spectroscopy, mechanism, and physical organic chemistry, OOL provides an opportunity to review and probe every basic chemical concept we can imagine in every chemical field. For instance, why are the pKa values of amino acids what they are? What would happen if they are different? Or the famous question; why did nature choose phosphates, a question which leads us to basic discussions of nucleophilicity, pKa, steric effects, thermodynamics, kinetics, atomic sizes and myriad other fundamental concepts. Other questions may include: Why alpha amino acids? Why ribose? Why these twenty amino acids and not others? We will never know the ultimate answers to these questions (since there was a fair element of chance involved), but simply asking them forces us to re-evaluate fundamental concepts of chemistry, an exercise that can be enormously rewarding and informative. OOL has involved fundamental research on chirality, self-assembly (more on this in the next point) and free energy calculation. This leads us from not knowing anything to fine-tuning our understanding and knowing something. As a side-benefit, then when there are some fanciful-sounding announcements, we can count on this knowledge to provide answers and level informed criticism.

3. OOL forces us to understand self-assembly: From a practical standpoint this may be the greatest benefit of OOL research. Self-assembly is undoubtedly the single-most important process in life's beginnings, and it also turns out to be of paramount importance in understanding everything else, from how Alzheimer's disease proteins fold to how surfactants sequester dirt to how we can construct supramolecular architectures for solar energy research. The workhorse in self-assembly is our cherished friend the hydrogen bond. Understanding the hydrogen bond thus opens the door to understanding self-assembly. In the past few years we have gained extremely valuable insights into hydrogen bonding, partly obtained through OOL research. For instance, studies of hydrogen bonding in DNA base pairing has revealed the subtle interplay between thermodynamics and electrostatics that stabilizes nucleic acids. Similar effects naturally operate in protein folding. The knowledge gained from such studies can help in the design of everything from novel proteins to supramolecular arrays. The same kind of self-assembly leads to insights into OOL questions addressing fundamental issues such as the formation of the first cell. The practical applications of self-assembly and OOL are thus two ends of a cycle which feed into each other, contributing and utilizing important insights that would fuel both basic and applied research. Understand self-assembly and you will not only inch closer to understanding origins but will also be able to harvest knowledge from the field toward practical ends.

4. OOL is the ultimate open-ended problem: Technically most problems in science are open-ended, but OOL is literally a problem without end. There is no conceivable way in which we will hit on the single, unique solution that jump-started life at a molecular level. We can inch tantalizingly closer to the plausible, but there is still a gigantic leap between the plausible and the certain. Should we despair? Absolutely not. If science can be defined as the "endless frontier", then OOL is the poster child for this definition. OOL will promise us an unending string of questions and plausible explanations until the end of the human species. This will bring us a proliferation of riches in basic chemical understanding. As scientists in general and chemists in particular, we should be ecstatic that OOL has given us a perpetual question machine to do research, discuss, debate and do more research. OOL like few other questions in science promises an infinitude of moments for reveling in the pleasure of finding things out.

And ultimately of course, OOL will help us take one more modest step in answering the question which human beings have asked since eternity- "Where do we come from?"

What more could we want?

Slices from the literature

1. A decade ago, MIT biologist Robert Weinberg who has been a contender for the Nobel Prize for his discovery of oncogenes wrote a seminal article in Cell called "The Hallmarks of Cancer". This article which became the highest cited article in Cell ever laid out the myriad ways in which a cell circumvents normal regulatory mechanisms to metamorphose into a monster. Weinberg and co-author Hanahan now follow up with a second "Hallmarks of Cancer" review in Cell to take stock of the ensuing decade's major discoveries and their implications for our understanding of cancer. It's a must read.

2. GPCR drugs: Magic bullets or magic "shotguns"? Over the last few years, the traditional paradigm of drug discovery laid out a century ago which posits that the ideal drug should be a "magic bullet" hitting a single protein target has been revised. While selectivity is still a valuable property, the importance of "selectively non-selective" drugs that hit a chosen subset of proteins is now much appreciated. No other family of drugs exemplifies this new paradigm more than CNS drugs which usually work by acting on a judicious set of GPCRs like those for serotonin, dopamine and norepinephrine. These compounds have been called "magic shotguns" and the general mechanism has been termed "polypharmacology".

However we are still light years away from actually designing such drugs which hit a pre-decided family of proteins on demand; a lot of the selective non-selectivity in these molecules has been designed in serendipitously and discovered in retrospect. The first step towards this goal would be to develop biochemical tools that would allow us to asses the exact polypharmacological activity of such compounds. UNC pharmacologist Bryan Roth details magic shotguns and efforts to unravel their complexities in a comprehensive review.

3. Directed evolution has been a valuable approach to speed up sluggish natural evolutionary processes to produce diverse libraries of biomolecules for functional screening. Here's a nice new review on using directed evolution to dissect protein-protein interactions which are of intense current interest.

4. And finally, a look at the human kinome and its interactions using a combination of sequence-based and ligand-based similarity methods. When each approach is limited, simply combine the two.

When Iron and Bacteria tragically collide: From the Middle Ages to the University of Chicago

Science brings us the bizarre, tragic but medically fascinating story of Malcolm Casadaban, a microbiologist working with plague bacteria at the University of Chicago, who died unexpectedly in 2009 of a then-unexplained cause. Obvious culprits were the plague bacteria he worked with. But the bacteria had been specially attenuated to be harmless in humans. So how could they kill?

It turned out that Casadaban had been the victim of an unfortunate double coincidence where two extremely rare causes combined to produce a lethal combination. It turns out that the plague bacteria he was working with had been rendered impotent by knocking out specific proteins which metabolize iron. More specifically they were engineered by knocking out a gene called pgm which codes for a protein allowing the bacterium to absorb iron from its surroundings. Iron is as essential to bacteria as it is to humans, and in the absence of iron-absorbing proteins the bacteria were useless as pathogens. Except that in this case they were not. Casadaban also suffered from hemochromatosis, a rare genetic disorder known for hundreds of years that causes the body to lock down stores of iron resulting in iron overload. From here it's not hard to put two and two together; when the iron-starved bacteria were suddenly introduced to Casadaban's body and its ample stores of the metal, they came to life like Frankenstein resurrected. The sudden windfall of virtually infinite stores of iron gave them the nutrient they lacked, transforming them into a fatal force that killed Casadaban.

Very unfortunate, but utterly fascinating from a medical standpoint. The reason I find it even more interesting is that it seems to at least superfically contradict an equally fascinating story from the Middle Ages, and in the process provides a plausible explanation for what happened. There is a remarkable and horribly tragic piece of history that possibly supports the evolutionary benefit of a debilitating condition like hemochromatosis. In the Middle Ages, when the Black Death struck Europe on a terrible scale, Jews were often accused of bringing this malady into people's homes through some kind of mystic powers. Thousands of Jews were killed for the sake of this superstitious belief. And the fact that Jews as a population seemed to be less affected by the plague only encouraged the paranoia and madness. One of the reasons that's traditionally offered for this relative immunity is the hygenic kosher conditions which Jews practised which made their homes less attractive to rats. But another hypothesized factor is the higher prevelance of the hemochromatosis gene among Jews, especially Ashkenazi Jews who are widespread among Jewish communities. It seems that just like other bacteria, the plague bacterium Yersinia pestis needs iron to survive. By locking up iron stores, the bodies of Jewish individuals denied this valuable nutrient to Yersinia, which made the germ less successful in colonizing its victims. Thus hemochromatosis, while causing harm by storing excessive iron, might have compensated for that harm by serving as a defense against the deadly plague. This theory is quite controversial and may indeed be wrong, but it underscores the basic point that diseases which may seem to be presently harmful could have served a useful purpose in the past by defending against infections. Since Yersinia is largely no longer a concern in the modern world because of medical advances, we see only its ugly side.

But this seems to contradict what we have just heard. If hemochromatosis could deny iron to iron-starved plague bacteria in the Middle Ages, how could the same condition have the opposite effect on even more iron-starved bacteria in Casadaban's body? I don't know the answer, but a plausible explanation is that the ultra iron-starved, genetically engineered bugs simply evolved to be much more efficient at scavenging iron from Casadaban's cells than normal plague bacteria. We have all seen how the phosphorus-starved bacteria in the arsenic fiasco are widely thought to have evolved an ability to mop up and zealously guard phosphorus stores even more efficiently. When the going gets tough, the tough gets going, especially in the bacterial world. It is well-documented how remarkably fast bacteria can evolve their biochemical machinery to tide over unfavorable circumstances and efficiently utilize low concentrations of essential nutrients down to the last atom. It won't be suprising at all if the impotent bacteria in Casadaban's unfortunate body simply retooled to forcefully rip out iron from his cells and proliferate. A small, routine step for bacteria with giant, terrible implications for a human being.

What an unfortunate story, but it's implications are utterly sobering. It tells us how much we still don't understand about the risks of modifying genomes of simple organisms. Genetically engineered organisms can combine with naturally engineered human bodies in bizarre, unexpected and tragic ways. We may have started to come to terms with the synthetic modification of life, but we still have a long way to go before we understand how the different parts of the natural and artificial worlds dynamically interact with each other in ways that we cannot anticipate. There's miles to go before we can sleep.