The cult of organic synthesis

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 Wöhlerdid 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 betweenWöhler'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 cult of psychology. There is a truly seductive feeling of power in being able to synthesize a substance like chlorophyll whose constitution 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 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 itnoted 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 andcapricious 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 routinely being 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 thescience 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.

"Quantum Man"

I still remember the day when, as a kid, I first came across the irrepressible Richard Feynman's memoirs "Surely you're joking Mr. Feynman". Within a few hours I was laughing so hard that tears were coming out of my eyes. Whether he was fixing radios 'by thinking', devising novel methods of cutting string beans in a restaurant or cracking the safes at Los Alamos, Feynman was unlike any scientist I had ever come across. Feynman died in 1988 and James Gleick's engaging and masterful biography of him appeared in 1993. Jagdish Mehra's dense, authoritative scientific biography came out in 1996. Since then there has been a kind of "Feynman industry" in the form of tapes, books, transcripts, interviews and YouTube video clips. While this has kept Feynman alive, it has also turned him into a kind of larger-than-life legend who is more famous in the public mind for his pranks and other exploits than for his science. Most laymen will tell you that Feynman was a brilliant scientist but would be hard-pressed to tell you what he was famous for. It's time that we were again reminded of what most contributed to Richard Feynman's greatness- his science. Lawrence Krauss's biography fulfills this role. You could think of Gleick's biography as a kind of Renaissance painting, an elaborate piece of work where he gets everything accurate down to the eyebrows of the men, women and Gods. Krauss's biography is more like the evocative impressionistic art of the French masters, more of a lucid sketch that brings out the essence of Feynman the scientist.

The biography is essentially aimed at explaining Feynman's scientific contributions, their relevance, importance and uniqueness. Thus Krauss wisely avoids pondering over oft-repeated details about Feynman's personal life. He compresses descriptions of Feynman's childhood, the tragic story of his first wife's death and their extremely touching relationship and his time at Los Alamos into brief paragraphs; if we want to learn more we can look up Gleick or Feynman's own memoirs. What concerns Krauss more than anything else is what made Feynman such a great scientist. And he delivers the goods by diving into the science right away and by explaining what made Feynman so different. Perhaps Feynman's most unique and towering ability was his compulsive need to do things from scratch, work out everything from first principles, understand it inside out and from as many different angles as possible. Krauss does a great job in bringing out this almost obsessive tendency to divine the truth from the source. It manifested itself at a very early age when Richard was cranking out original solutions to algebra and arithmetic problems in school. And it was paramount in his Nobel Prize winning work.

Krauss succinctly explains how this intense drive to look at things in new ways allowed Feynman to do novel work during his PhD with John Wheeler at Princeton in which he formulated theories that described antiparticles as particles traveling backwards in time. Later Feynman also applied the same approach in using a novel method based on the principle of least action to explain the dizzying mysteries of quantum electrodynamics. Krauss does an admirable job in explaining the physics behind these contributions in layman's terms. Feynman's "sum over histories" prescription involved taking into consideration all of the infinite paths that a particle can take when getting from the beginning to the end point. This was a bizarre and totally new way of looking at things, but then quantum mechanics is nothing if not bizarre. As Krauss describes, the moment of revelation for Feynman came in a meeting where, using his techniques and intellectual prowess, he could finish in a few hours a complicated calculation for mesons that had taken another researcher several months. Krauss also narrates how Feynman brought the same freewheeling, maverick approach to thinking about superfluidity, beta decay, the strong nuclear force, gravity and computing and the book contains the most complete popular scientific treatments of Feynman's thoughts about these important problems that I have seen. The approach did not always work (as it did not in case of superconductivity) but it encouraged other physicists to think in new ways. In fact as Krauss lucidly narrates, Feynman's great influence on physics was not just through the direct impact of his ideas but also through the impact of his unconventional thinking which inspired students and other scientists to think outside the box.

As scientifically brilliant as Feynman was, Krauss also does not gloss over his professional and personal flaws and this biography is not a hagiography. Professionally, Feynman's independent spirit meant that he often would not read the literature and would stay away from mainstream interests which his colleagues were pursuing; while this greatly helped him, on more than one occasion it led to him being scooped. At the same time Feynman also did not care about priority and was generous in sharing credit. As for mentoring, while Feynman was a legendary teacher by way of example, unlike his own advisor John Wheeler he left few bonafide graduate students because of his compulsive tendency to solve problems himself. On a personal basis, probably the most shocking description concerns Feynman's womanizing. It's hard to say how much of it is true, but Krauss describes Feynman's affairs with colleagues' wives, his elaborate methods to seduce women in bars and the personal and emotional entanglements his womanizing caused. At least one fact is jarring; apparently when he was a young professor at Cornell, the boyish-looking Feynman used to pretend to be a graduate student so he could date undergraduates. This kind of behavior would almost certainly lead to strict disciplinary action in a modern university, if not something more drastic. In his early days Feynman was also known for not suffering fools gladly, although he mellowed as he grew older. Later on Krauss details Feynman's more publicly known activities, including his bongo playing, nude painting and his famous demonstration of the failure of the O-rings in the Challenger space shuttle disaster. Feynman's absolute insistence on honesty and truth in science and on reporting the negative results along with the positive ones also comes across, and should be a model for modern scientists. The biography does a good job of demonstrating that in science, true success needs fearlessness, determination and an unwavering belief in your ideas.

Ultimately, it's not Feynman's bongos, nude art and relentless clowning that make him a great man. However, since his death, he has often been perceived that way by the public largely due to the industry that has grown up around him. But Richard Feynman was defined first and foremost by his science and his striking intellectual originality that allowed him to look at the physical world in wholly unanticipated new ways. Krauss's biography performs a timely and valuable service in reminding us why, when we talk about Feynman, we should first talk about his physics.

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 reportdetailing 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.

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, transofrming 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.