"Didn't they make Einsteinium?"..."No, you SOLVATE the excited state"..."I did a really bad-ass Grubbs on that baby"..."You can molecular dynamics that to hell and it still won't help".
Yes, ACS meetings can be pretty nice. I almost forgot.
Next week I am attending and giving a talk at the ACS National Meeting in Boston. Lots of interesting presentations, but the unusual title of one talk in particular caught my eye:
"Was plagiarism involved in the development of the Woodward—Hoffmann rules?"
Jeffrey I. Seeman Ph.D.
That sounds like fun! I am guessing the answer is going to be 'no'. It's in Room 205A/B on Monday, August 23rd.
In the middle of all that disappointing news about failed treatments targeting beta-amyloid, here's some silver lining. A lot of people think that the real reason all these drugs are not fighting AD is not because they are ineffective per se but because they are administered too late, long after the disease has manifested itself. Thus the logical step toward making these therapies more effective would be in detecting AD earlier. In the last few months, a slew of articles has detailed several techniques for diagnosing AD early which look promising, from better brain imaging to spinal taps. An article in today's New York Times looks at the integrated effort that has spawned these developments. It turns out that the effort has come about from several government agencies, universities, non-profit organizations and imaging and pharmaceutical companies collaborating to find early biomarkers for AD. The joint initiative has pooled together several million dollars from each contributor. As everyone wisely realized, AD is much too complex to be tackled by single research entities (what disease isn't?). As one participant said:
"We all realized that we would never get biomarkers unless all of us parked our egos and intellectual-property noses outside the door and agreed that all of our data would be public immediately.”
"Parking their egos" outside would be necessary for the diverse and large studies required to gain insight into true AD biomarkers.
“The problem in the field was that you had many different scientists in many different universities doing their own research with their own patients and with their own methods,” said Dr. Michael W. Weiner of the San Francisco Department of Veterans Affairs, who directs ADNI. “Different people using different methods on different subjects in different places were getting different results, which is not surprising. What was needed was to get everyone together and to get a common data set.” But that would require a huge effort. No company could do it alone, and neither could individual researchers. The project would require 800 subjects, some with normal memories, some with memory impairment, some with Alzheimer’s, who would be tested for possible biomarkers and followed for years to see whether these markers signaled the disease’s progression.
The problem is of course is that it can be tricky as hell to distinguish true biomarkers from spurious ones (the old problem of distinguishing correlation from causation). It would take some time to zero in on those biomarkers that truly signal the onset of the disease. But this bit of news is gladdening for two reasons; firstly because it indicates that people are perhaps moving away from the obsession with targeting amyloid (which nonetheless continues to be a fascinating entity), and more importantly because it indicates that there are still people willing to park their egos outside the door and publicly collaborate to address a very complex medical challenge. Hopefully this endeavor should provide inspiration for tackling other diseases.
1. Snake venom protein specificity explained through differences in protein dynamics probed by molecular dynamics simulations.
2. A 'new' interaction discovered in protein structures? The lone pair of a C=O oxygen can interact with the anti-bonding orbital of another C=O bond. Do we need to incorporate this interaction into force fields yet?
3. Rosetta performs another impressive feat, this time designing a Diels-Alderase enzyme from scratch that performs a bimolecular DA reaction
4. Sir Charles Mackerras, one of the finest interpreters of Mozart, is dead at 84. I was not aware that he played such a prominent role in bringing Leos Janacek's operas to the West.
5. An extremely well-written and comprehensive account of the (healthy) controversy over the exact binding site of drugs binding to the M2 proton channel protein in the influenza virus. As the post says, this is exactly how good science progresses, and we all benefit from such spirited to-and-fro.
Sixty-five years ago, after learning that a friend who was reported missing after the bombing of Hiroshima had turned up in a hospital there, my mother put together a meager care package and set out from our home in Shikoku to pay a visit. When she returned, she shared her friend’s description of that morning in August 1945.
Moments before the atomic bomb was dropped, my mother’s friend happened to seek shelter from the bright summer sunlight in the shadow of a sturdy brick wall, and she watched from there as two children who had been playing out in the open were vaporized in the blink of an eye. “I just felt outraged,” she told my mother, weeping.
Even though I didn’t fully grasp its import at the time, I feel that hearing that horrifying story (along with the word outrage, which put down deep, abiding roots in my heart) is what impelled me to become a writer. But I’m haunted by the thought that, ultimately, I was never able to write a “big novel” about the people who experienced the bombings and the subsequent 50-plus years of the nuclear age that I’ve lived through — and I think now that writing that novel is the only thing I ever really wanted to do.
In Edward W. Said’s last book, “On Late Style,” he gives many examples of artists (composers, musicians, poets, writers) whose work as they grew older contained a peculiar sort of concentrated tension, hovering on the brink of catastrophe, and who, in their later years, used that tension to express their epochs, their worlds, their societies, themselves.
As for me, on the day last week when I learned about the revival of the nuclear-umbrella ideology, I looked at myself sitting alone in my study in the dead of night . . . . . . and what I saw was an aged, powerless human being, motionless under the weight of this great outrage, just feeling the peculiarly concentrated tension, as if doing so (while doing nothing) were an art form in itself. And for that old Japanese man, perhaps sitting there alone in silent protest will be his own “late work.”
I was going to first describe Rosetta in a post, but a rather cool paper related to the program which appeared in Nature yesterday makes me jump the gun.
In a nutshell, Rosetta tries to predict the structure of proteins from amino acid sequence by inserting fragments from known protein structures and doing many rounds of side chain torsional angle and rigid-body energy optimization. It uses a scoring function to rank the resulting structures that uses empirically derived hydrogen bonding, hydrophobic burial and desolvation terms. Detailed description will have to await the next post since yesterday's paper is not about Rosetta per se.
Instead the paper talks about a program named FoldIt which essentially asks relatively untrained computer gamers to address the protein folding problem. Gamers are asked to tweak, pull, freeze and rotate parts of an incorrectly folded structure to try to twist it into the correct structure. The interface looks like the picture above. Data from a total of 57,000 gamers was pooled. The gamers were driven to solve the problem by the usual incentives of competition and co-operation. Each set of movements would lead to an increase or decrease in a score, with the goal being to find the correct folded structure corresponding to the minimum score. The corresponding set of operations in Rosetta would involve hydrophobic burial, hydrogen bond formation and breakage, helix rotation and other related movements. The project essentially pitted Rosetta versus the gamers.
The results were striking. In a significant number of cases, the gamers actually outdid Rosetta. The reasons are very intriguing and- in an age where computers seem to have unlimited power over our lives- generally testify to the advantages of humans being over computers. For instance in one case, the gamers had to first unravel significant parts of the protein leading to a sharply unfavorable score and then again re-fold it, leading to a correct structure. Rosetta would not attempt the first operation because of the sharp increase in score. This is a classic example of long-term strategy. Unlike computers, humans can make seemingly bad short-term decisions that ultimately lead to good results; we observe this process in many aspects of daily life, from stock market traders taking risks because they see favorable returns later, to politicians making unpopular choices because they think these choices will eventually lead to a popular outcome. Unlike humans though, it is very difficult for a computer program to do long-term planning, and this example illustrates not only the advantages that human intuition can have but also identifies gaps in a program like Rosetta which can possibly be filled.
Another example where the humans outdid the computers was when presented with a set of 10 incorrect structures. Humans generally chose the structure closest to the given structure, whereas Rosetta picked another structure. The main point here is that simple visual clues can sometimes trump complicated decision-making (although they can also mislead). More generally, the results underscored the fact that gut feelings and mere inspection can sometimes lead to successful results.
The one case where the humans did not do as well as Rosetta was in addressing the "classic" protein folding problem, where the challenge was to predict 3D structure from sequence alone. In this case, the sheer amount of conformational space to be searched thwarts success, and there are also no visual cues to guide the process unlike before. The key value of computer approaches which can rapidly pare down the conformational space becomes evident in this example.
So since humans outdid the computer in many cases on the basis of intuition, this must be one super-smart group of biochemists, right? Au contraire! One of the most compelling facts was that most of the gamers in fact not only lacked a formal background or PhD. in biochemistry, but also lacked a formal background in science. Relatively few had college degrees, let alone more advanced ones. For instance there is a profile of a woman in the video below who works in a physical therapist's office, who says that after coming home she feels like a different person when she plays the game. This is great. The examples strikingly illustrates that even untrained humans can possess skills that may be difficult to program into a computer.
It remains to be seen if these results can be extrapolated to large-scale trials, but this very intriguing study perhaps illustrates the general principle that cracking a problem as complex as protein folding is going to require a diverse set of skills, from Monte Carlo searching to gut feelings.
Cooper, S., Khatib, F., Treuille, A., Barbero, J., Lee, J., Beenen, M., Leaver-Fay, A., Baker, D., Popović, Z., & players, F. (2010). Predicting protein structures with a multiplayer online game Nature, 466 (7307), 756-760 DOI: 10.1038/nature09304
"Every man, woman and child lives under a nuclear sword of Damocles, hanging by the slenderest of threads, capable of being cut at any moment by accident, or miscalculation, or by madness. The weapons of war must be abolished before they abolish us.”- John F. Kennedy, speech to the UN, September 1961.
"Countdown to Zero" is one of the best accounts of the dangers of nuclear weapons for the layman that I have recently seen. The film which opened last week takes a comprehensive yet succinct look at the risks posed by nuclear weapons, and is set against the backdrop of John F. Kennedy's speech to the United Nations in which he quoted the words cited above. JFK talked about a "Sword of Damocles" hanging on our head that is secured by a flimsy thread. As the film emphasizes, the most important operative words in Kennedy's speech are "accident, miscalculation or madness" which can all cut the thread holding the sword. To illustrate how this could happen, the film showcases interviews with leading arms control experts and policy personnel, including former CIA agent Valerie Plame, Harvard professor Matthew Bunn, nuclear terrorism expert Graham Allison, WMD expert Joseph Cirincione and world leaders like Mikhail Gorbachev and Tony Blair.
The fact is that no matter how responsible the leaders of countries with nuclear weapons may be and how well-protected the weapons may seem, the extremely complex nature of the system always increases the chances of miscalculation, accident or madness. The film gives concerning examples. For instance, a few years ago, nuclear weapons instead of regular ones were loaded on a plane in North Dakota and flown almost halfway around the country without anyone noticing it. The Cuban Missile Crisis is of course well-known, lesser known are the Palomares incident and half a dozen others when nuclear weapons were accidentally dropped from mid air. Fortunately none detonated. But the danger is pervasive and the film also recounts some chilling events. The most heart-stopping is an incident in 1995 recounted by Cirincione, when the Russians mistook the flight of an experimental rocket from Norway for a nuclear launch. The codes were ready, everyone in the Russian hierarchy was convinced, and all that remained to launch a nuclear strike against the US was President Yeltsin's approval. Thankfully for the world, Yeltsin was "not drunk" and he did not trust the officials' judgment enough, leading to a narrow brush with catastrophe. The problem is that the complex protocols embedded in the use of nuclear weapons allow much opportunity for misunderstandings and accidents and very little time for response and corrective action. Even a President would have typically no more than a few minutes to make a decision, thus increasing the possibility of triggering armageddon. The simplest and most ludicrous of causes can set off false alarms; in one case, the setting off of a nuclear alert was the result of a malfunction in a single computer chip costing less than a dollar.
One of the most jaw-dropping instances I remember was from Richard Rhodes's book. Zbigniew Brzezinski, Jimmy Carter's National Security Advisor, was woken up in the middle of the night and told that there were 1500 Soviet nuclear missiles headed for the US. As Brzezinski was contemplating what to do next, the caller called back and said that the number of missiles had been upgraded to 15000. Hearing this, Brzezinski just sat on his bed; there would be no point in alerting anyone. Of course, it turned out to be "computer malfunction".
Apart from such misunderstandings, the other reason why nuclear weapons pose such a great danger is of course because they may fall into the hands of terrorists, and deterrence does not apply to such stateless actors. Al Qaeda has been trying to get their hands on nukes for years. What makes the situation worse is the relatively easy accessibility of enriched uranium in the former Soviet Union. After the Cold War ended, many nuclear facilities in the former Soviet republics found themselves orphaned, severed from central control, with their workers out of a job. While many of the facilities were later secured with US cooperation, many others were ludicrously insecure, with barely a padlock preventing access to nuclear material; in the words of a former Soviet official, "potatoes were guarded better". Selling a few grams of uranium to potential buyers would allow impecunious laid-off workers from these facilities to make a lucrative buck. The film documents that there have been literally dozens of instances when former nuclear workers have been caught trying to smuggle a few grams of nuclear material across borders in Russia and Central Asia. In addition, countries like Iran, North Korea and Pakistan are happy to trade nuclear-related technology to wannabe buyers.
This nuclear material is notoriously hard to detect. As the film says, smuggling a few kilograms of enriched uranium by shielding it in a lead pipe is child's play. This is mainly because the relatively weak radiation from uranium can be almost completely shielded by lead, but also because this uranium could be hidden in any one of a whopping 100,000 shipping containers entering the US every single day. Finding a few kilos of U-235 in a heavily shielded lead casing in one of these countless containers is an unimaginably difficult problem to solve. Set the detectors on high and one would not detect the low-intensity radiation. Set it on low and one would detect almost everything else (including fruits, papers and wood) which emit comparable ambient levels of radiation.
If terrorists manage to get past the most difficult step of acquiring nuclear material, they can easily build a crude nuclear bomb. Plus, paraphrasing Churchill, terrorists don't have to do their best, they just have to do enough. Exploding a crude bomb in the port itself would not be what they have in mind, but it would still be enough to bring about chaos and panic, possibly collapsing the financial and economic system of a country.
So what can be done to address this life-threatening problem? One of the biggest truisms about nuclear weapons which separates them from other WMDs is that if you don't have uranium or plutonium, you cannot build these weapons, period. Thus in theory, you completely solve the problem if you secure the material. Programs for securing material from the former Soviet republics have been instituted for years, but funding has embarrassingly been a problem. Plus there is no accurate estimate of how much material may have been stolen after the Soviet Union collapses. Securing this material would be the first thing to do. Secondly, countries who want to peacefully pursue atomic energy must be provided nuclear material by an international body under the strictest of safeguards.
But most importantly, there is one almost perfect solution which there is no getting around: reduce the nuclear arsenals of the world to zero. Nada. Zilch. There is no doubt that the US and Russia which still stock the lion's share of nukes should take the lead, a point which has been belabored often to scant effect. This should especially be ludicrously easy for the US which still has thousands of nukes on hair-trigger alert and which has conventional forces that could easily overwhelm any other country's defenses and offenses. If there is one country that does not need any nuclear weapons, it's the US, followed by Russia. The psychological impact of the US renouncing every single nuclear weapon would be hard to overestimate (Nixon did it with chemical and biological weapons in the 70s). It would be tremendous and would offer the US an unprecedented moral authority to ask others to do the same. While it may not be easy for countries like India and Israel which share extensive boundaries with unstable and dangerous regimes, such an act will signify huge potential. This was a dream that President Reagan often talked about. As idealistic as it sounds, it should be feasible at least for the US. Most refreshingly, amid all the partisan bickering that we keep hearing about, such an initiative has gained traction with a wide swathe of influential statesmen from both parties. In a compelling document last year, several former highly influential bipartisan officials like Henry Kissinger, George Schultz, William Perry and Sam Nunn called for the abolishment of nuclear weapons. President Obama has latched on to this dream. It remains to be seen what he actually does about it.
As JFK said in his speech, "the weapons of war must be abolished before they abolish us". In 1986, during the very promising Reykjavik meeting when Reagan and Gorbachev came within a hairsbreadth of getting rid of all nuclear weapons, Reagan told Gorbachev about a dream that seems straight out of a movie. He said that once the world has decided to get rid of all nuclear weapons, he and Gorbachev would meet again in Reykjavik, each holding the last nuclear missile in their hands. They would both be so old that they would hardly recognize each other. Gorbachev would squint at Reagan and say "Ron, is that you"?. And Reagan would say, "Mikhail?". And then they would both destroy the last two nuclear bombs on the planet, and the whole world would have a giant party.
The 'combinatorial explosion' problem generally refers to the difficulty of locating a unique solution to a given problem when the potential space of solutions to be searched is astronomically large. It is found in many areas of science but most notably in protein folding where it takes the name of "Levinthal's Paradox". Biochemist Cyrus Levinthal pointed out in the 60s that if a given sequence of amino acids were to explore every possible conformation for each of its amino acids, even a small protein of 100 amino acid residues or so would take a time longer than the age of the universe to find the correct folded structure.
The paradox is clearly not a paradox since nature has solved the problem of protein folding countless number of times since life began on this planet (this is the protein-centric version of the anthropic principle). Thus, the combinatorial 'problem' is not a problem so far as we know that a robust and tried-and-tested solution exists and in fact has been used by nature to stunning effect. The problem is really to figure out the devilish details of this solution. In the past 30 years or so scientists have employed a battery of experimental and theoretical techniques to tackle the issue. Many important insights have revealed that understanding the factors that dictate the self-assembly of proteins can lead to great insights into the problem. Probably the foremost among these factors is the hydrophobic effect, which productively buries greasy chemical functionalities in the interior of proteins utilizing the multiple driving engines of favorable desolvation, entropic expulsion of water and weak packing-induced interactions. Other important factors ubiquitously used by nature include hydrogen bonds and salt bridges.
The key insight in tackling the problem has been to realize that protein folding or protein-protein interactions or indeed, all the myriad biomolecular interactions that occur in the cellular milieu, do not arise 'by chance'. Once we get past this stumbling block, things make a lot of sense. Chance events undoubtedly keep on happening, but nature preferentially preserves the consequences of certain events. Thus, similar motifs which have been successfully used for certain proteins are used for others. Nature does not need to keep on searching all of conformational space again and again for generating new structures. The analogy would be in designing a new house based on existing structures like bricks, arches and beams rather than designing it from scratch. A Victorian Englishman coined a word for this process of preservation of favorable elements leading to new biological entities a hundred and fifty years ago- natural selection. Thus, the protein folding problem can be immediately demystified when one realizes that natural selection keeps on using recurring motifs to build new structures. Far from being a chance event, the complexity of life can be explained by the re-use of pre-existing structures to build complexity. It may seem highly improbable and miraculous, but Darwin's genius was to provide a mechanism for precisely explaining this illusion of 'design', both on macro and molecular scales. It no longer seems improbable, but instead offers us a tool of incomparable power to peek into the heart of complex biological phenomena.
From a chemist's point of view, natural selection at the molecular level takes the form of the preservation of low-energy conformations of biomolecules that may possess other qualities such as stability, catalytic proficiency and rapid replication. Such chemical entities (think 'DNA') will persist and proliferate and they will be used in multiple designs. Consider coiled-coil structures with their typical seven-residue amino acid motifs or the catalytic triad that cleaves peptide bonds in proteases. Or think of something that's bleedingly simple- the phosphate group which, by virtue of its remarkable qualities of 'transient stability' to hydrolysis, proves to be the perfect connection for life's lego pieces. Once nature hit upon such designs, they could be easily employed in many different structures, dramatically reducing the amount of functional space to be searched. From a chemical perspective, the key property of these favored motifs is self-assembly which is driven by many well-understood physicochemical factors such as the aforementioned hydrophobic effect. Self-assembly, surely one of the greatest inventions of the laws of physics and chemistry, took the problem of the origin of life from miraculous impossibility to tantalizing possibility.
If nature can use pre-existing functionalities to solve the protein folding problem, why can't we do the same? Indeed, many theoretical approaches to protein folding have adopted this kind of approach. Probably the foremost algorithm for predicting protein folding today is a suite of programs called Rosetta which was originally developed by David Baker's group at the University of Washington. In a competition to predict protein structures in 2001, the program did so well that it was compared by a very famous computational chemist named Peter Kollman to Babe Ruth's world record, when even the second-best competitor was woefully lagging behind.
In the next post we will take a look at this program and why it works so successfully.
