The Curious Wavefunction

Chemistry, fluid dynamics and an awful radioactive mess

noreply@blogger.com (Wavefunction) — Fri, 10 May 2013 01:19:00 +0000

When it comes to handling radioactive waste the Hanford site in western Washington state is the opposite of a role model. Ever since its reactors started producing the plutonium which was used in the Nagasaki bomb, Hanford has been generating waste with little foresight and responsibility. It has the dubious honor of being the most contaminated radioactive site in the country.

Scientific American has an article which gives an idea of how truly awful the problem is. It's not just that there's a lot of waste or that it's everywhere. It seems like the waste basically conforms to the devil's definition of the word "heterogeneous" and takes a form representing the average nuclear chemist's version of hell:

"Overall, the waste tanks hold every element in the periodic table, including half a ton of plutonium, various uranium isotopes and at least 44 other radionuclides—containing a total of about 176 million curies of radioactivity. This is almost twice the radioactivity released at Chernobyl, according to Plutopia: Nuclear Families, Atomic Cities, and the Great Soviet and American Plutonium Disasters, by Kate Brown, a history professor at the University of Maryland, Baltimore County. The waste is also physically hot as well as laced with numerous toxic and corrosive chemicals and heavy metals that threaten the integrity of the pipes and tanks carrying the waste, risking leakage.

The physical form of the waste causes problems, too. It’s very difficult to get a representative sample from any given tank because the waste has settled into layers, starting with a baked-on “hard heal” at the bottom, a layer of salt cake above that, a layer of gooey sludge, then fluid, and finally gases in the headspace between the fluid and the ceiling. Most of the radioactivity is in the solids and sludge whereas most of the volume is in the liquids and the salt cake."

"Plutopia", by the way, is a very interesting book. In any case, the waste problem at Hanford looks like it will engage the services of every conceivable kind of chemist, engineer and fluid dynamics expert that I can imagine.

"All of these considerations contribute to the overall problem, which can be summed up in one word: flow. To get to the glass log stage the waste has to travel through an immense labyrinth of tanks and pipes. It has to move at a fast enough clip to avoid pipe and filter clogs as well as prevent solids from settling. This is quite a challenge given the multiphasic nature of the waste: solids, liquids, sludge and gases all move differently. The waste feed through the system will be in the form of a “non-Newtonian slurry”—a mixture of fluids and solids of many different shapes, sizes and densities. If the solids stop moving, problems ensue."

The article also talks about two serious concerns; the possibility that enough plutonium in the waste could build up to trigger a chain reaction (although one which in bomb parlance would be a "fizzle") and the possibility that the heat and radiation could split water up and lead to a buildup of hydrogen. For now these concerns are about unlikely events and are secondary in any case to the much more important problems of Sludge Management and the Battle against Viscosity. Just tells you how important it is to nip problems with reactor waste in the bud before they turn into a godforsaken headache for future generations.

On synthesis, design and chemistry's outstanding philosophical problems

noreply@blogger.com (Wavefunction) — Wed, 08 May 2013 12:38:00 +0000

: Chemists need to move from designing structure - exemplified by this synthetic receptor - to designing function (Image: Max Planck Institute).

Yesterday I wrote a post about a perspective by multifaceted chemist George Whitesides in which he urged chemists to broaden the boundaries of their discipline and think of big picture problems. But the article spurred me to think a bit more about a question which I (and I am sure other chemists) have often thought about; what’s the next big challenge for chemistry?

And when I ask this question I am not necessarily thinking of specific fields like energy or biotechnology or food production. Rather, I am thinking of the next outstanding philosophical question confronting chemistry. By philosophical question I don’t mean an abstract goal which only armchair thinkers worry about. The philosophical questions in a field are those which define the field’s big problems in the most general sense of the term. For physicists it might be understanding the origin of the universe, for biologists the origin of life. These problems can also be narrowly defined questions that nonetheless expand the understanding and scope of a field; for instance in the early twentieth century physicists were struggling to make sense of atomic spectra, which turned out to be important for the development of quantum theory. It’s also important to note that the philosophical problems of a field change over time, and this is one reason why chemists should be aware of them; you want to move with the times. If you were a “chemist” in the sixteenth century the big question was transmutation. In the nineteenth century when chemistry finally was cast in the language of elements and molecules the big question became theconstitution of molecules in the form of atomic arrangements.

Synthesis is no longer chemistry’s outstanding general problem

When I think about the next philosophical question confronting chemistry I also feel a sense of despondency. That’s because I increasingly feel that the great philosophical question that chemists are going to face in the near future is emphatically not one whose answer they will locate in the all-pervasive activity that always made chemistry unique: synthesis. What always set chemistry apart was its ability to make new molecules that never existed before. Through this activity chemistry has played a central role in improving our quality of life.

The point is, synthesis was the great philosophical question of the twentieth century, not the twenty-first. Now I am certainly not claiming that synthesizing a complex natural product with fifty rotatable bonds and twenty chiral centers is even today a trivial task. I am also not saying that synthesis will cease to be a fruitful source of solutions for humanity’s most pressing problems, such as disease or energy; as a tool the importance of synthesis will remain undiminished. What I am saying is that the general problem of synthesis has now been solved in an intellectual sense (as an aside, this would be consistent with the generally pessimistic outlook regarding total synthesis seen on many blogs.)

The general problem of synthesis was unsolved in the 30s. It was also unsolved in the 50s. Then Robert Burns Woodward came along. Woodward was a wizard who made molecules whose construction had defied belief. He had predecessors, of course, but it was Woodward who solved the general problem by proving that one could apply well-known principles of physical organic chemistry, conformational analysis and spectroscopy to essentially synthesize any molecule. He provided the definitive proof of principle. All that was needed after that was enough time, effort and manpower. If chemistry were computer science, then Woodward could be said to have created a version of the Turing Machine, a general formula that could allow you to synthesize the structure of any complex molecule, as long as you had enough NIH funding and cheap postdocs to fill in the specific gaps. Every synthetic chemist who came after Woodward has really developed his or her own special versions of Woodward’s recipe. They might have built new models of cars, but their Ferraris, Porches and Bentleys – as elegant and impressive as they are – are a logical extension of Woodward and his predecessor’s invention of the internal combustion engine and the assembly line.

A measure of how the general problem of synthesis has been solved is readily apparent to me in my own small biotech company which specializes in cyclic peptides, macrocycles and other complex bioactive molecules. The company has a vibrant internship program for undergraduates in the area. To me the most remarkable thing is to see how quickly the interns can bring themselves up to speed on the synthetic protocols. Within a month or so of starting at the bench they start churning out these compounds with the same expertise and efficiency as chemists with PhDs. The point is, synthesizing a 16-membered ring with five stereocenters has not only become a routine, high-throughput task but it’s something that can be picked up by a beginner in a month. This kind of synthesis might have easily fazed a graduate student twenty years ago and taken up a good part of his or her PhD project. The bottom line is that we chemists have to now face an uncomfortable fact: there are still a lot of unexpected gems to be found in synthesis, but the general problem is now solved and the incarnation of chemical synthesis as a tool for other disciplines is now essentially complete.

Functional design and energetics are now chemistry’s outstanding general problems

So if synthesis is no longer the general problem, what is? My own field of medicinal chemistry and molecular modeling provides a good example. It may be easy to synthesize a highly complex drug molecule using routine techniques, but it is impossible, even now, to calculate the free energy of binding of an arbitrary simple small molecule with an arbitrary protein. There is simply no general formula, no Turing Machine that can do this. There are of course specific cases where the problem can be solved, but the general solution seems light years away. And not only is the problem unsolved in practice but it is also unsolved in principle. Sure, we modelers have been saying for over twenty years that we have not been able to calculate entropy or not been able to account for tightly bound water molecules. But these are mostly convenient questions which when enunciated make us feel more emotionally satisfied. There have certainly been some impressive strides in addressing each of these and other problems, but the fact is that when it comes to calculating the free energy of binding, we are still today where we were in 1983. So yes, the calculation of free energies – for any system – is certainly a general problem that chemists should focus on.

But here’s the even bigger challenge that I really want to talk about: We chemists have been phenomenal in being able to design structure, but we have done a pretty poor job in designing function. We have of course determined the function of thousands of industrial and biological compounds, but we are still groping in the dark when it comes to designing function. Here are a few examples: Through combinatorial techniques we can now synthesize antibodies that we want to bind to a specific virus or molecule, but the very fact that we have to adopt a combinatorial, brute force approach means that we still can’t start from scratch and design a single antibody with the required function (incidentally this problem subsumes the problem of calculating the free energy of antigen-antibody binding). Or consider solar cells. Solid-state and inorganic chemists have developed an impressive array of methods to synthesize and characterize various materials that could serve as more efficient solar materials. But it’s still very hard to lay out the design principles – in general terms – for a solar material with specified properties. In fact I would say that the ability to rapidly make molecules has even hampered the ability to think through general design principles. Who wants to go to the trouble of designing a specific case when you can simply try out all combinations by brute force?

I am not taking anything away from the ingenuity of chemists – nor am I refuting the belief that you do whatever it takes to solve the problem – but I do think that in their zeal to perfect the art of synthesis chemists have neglected the art of de novo design. Yet another example is self-assembly, a phenomenon which operates in everything from detergent action to the origin of life. Today we can study the self-assembly of diverse organic and inorganic materials under a variety of conditions, but we still haven’t figured out the rules – either computational or experimental – that would allow us to specific the forces between multiple interacting partners so that these partners assembly in the desired geometry when brought together in a test tube. Ideally what we want is the ability to come up with a list of parts and the precise relationships between them that would allow us to predict the end product in terms of function. This would be akin to what an architect does when he puts together a list of parts that allows him to not only predict the structure of a building but also the interplay of air and sunlight in it.

I don’t know what we can do to solve this general problem of design but there are certainly a few promising avenues. A better understanding of theory is certainly one of them. The fact is that when it comes to estimating intermolecular interactions, the theories of statistical thermodynamics and quantum mechanics do provide – in principle – a complete framework. Unfortunately these theories are usually too computationally expensive to apply to the vast majority of situations, but we can still make progress if we understand what approximations work for what kind of systems. Psychologically I do think that there has to be a general push away from synthesis and toward understanding function in a broad sense. Synthesis still rules chemical science and for good reason; it's what makes chemistry unique among the sciences. But that also often makes synthetic chemists immune to the (well deserved) charms of conformation, supramolecular interactions and biology. It’s only when synthetic chemists seamlessly integrate themselves into the end stages of their day job that they will learn better to appreciate synthesis as an opportunity to distill general design principles. Let the synthetic chemist interact with the physical biochemist, the structural engineer, the photonics expert; let him or her see synthesis through the requirement of function rather than structure. Whitesides was right when he said that chemists need to broaden out, but another way to interpret his statement would be to ask other scientists to channel their thoughts into synthesis in a feedback process. As chemists we have nailed structure, but nailing design will bring us untold dividends and will help make the world a better place.

First published on the Scientific American Blog Network.

George Whitesides on the responsibility of chemists and the future of chemistry

noreply@blogger.com (Wavefunction) — Mon, 06 May 2013 21:14:00 +0000

Catching up on a few articles I had missed, I came across a characteristically deep and wide-ranging essay called "Assumptions" by George Whitesides about science, its future and our responsibility as scientists. It's a very general and kaleidoscopic essay not restricted to chemistry, but the bits about chemistry, its role in understanding the major problems confronting humanity and chemists' responsibility in extending the scope of chemical science are quite thought-provoking:

Chemistry, by its culture, has been almost blindly reductionist. I am repeatedly reminded that “Chemists work on molecules”, as if to do anything else was suspect. Chemists do and should work on molecules, but also on the uses of molecules, and on problems of which molecules may be only a part of the solution. If chemists move beyond molecules to learn the entire problem—from design of surfactants, to synthesis of colloids, to MRI contrast agents, to the trajectories of cells in the embryo, to the applications of regenerative medicine—then the flow of ideas, problems, and solutions between chemistry and society will animate both.

Whitesides is clearly making a plea for chemists to become even more interdisciplinary than what they already are, to pursue not just the development of the solution but its application and integration; his own group provides a remarkable example of chemists, physicists, biologists and engineers working together on highly multidisciplinary problems. It's quite clear that to achieve this interdisciplinary expertise we have to completely break down the traditional barriers between synthesis, structure determination, biology and materials (in this world the professor who rejected my biochemical literature seminar topic because it "did not include any synthesis" would be an anachronism). The next paragraph makes clear the role of the "central science"

As a technology, chemistry has built the foundation from which many of the discoveries of “biology” or “microelectronics” or “brain science” (or “planetary exploration”, for that matter) have grown. There would be no genomics without chemical methods for separating fragments of DNA, and for synthesizing primers and probes, and for separating restriction endonucleases into pure activities. There would be no nuclear ICBMs without methods of refining plutonium, and making explosive lenses. There would be no drugs without synthesis and mass spectroscopy. There would be no interplanetary probes without fuels, and carbon/carbon rocket throat nozzles, and silicon single crystals.

And here's something about what the future of chemistry should be:

Those are the past. What about the future? Chemistry is, still, everywhere: It must be! It is the science of the real world. But to remain a star in the play rather than a stagehand, it must open its eyes to new problems. It is impossible that the human life span will increase dramatically without manipulation of the molecules of the human organism, but understanding this problem will require more than manipulating molecules. Communication between the living and non-living will require engineering a molecular interface between them, but designing this interface will require understanding the nature of “information” in organisms and in computers, and how to translate between them. A society that uses information technology to interweave all its parts requires new systems for generating, distributing, and storing power, but batteries will be only one part of these systems.

Chemistry has always been the invisible hand that builds and operates the tools, and sustains the infrastructure. It can be more. We think of ourselves as experts in quarrying blocks from granite; we have not thought it our job to build cathedrals from them. Whether we choose to focus on the molecules, materials, and tools that are at the beginnings of discovery, or bring our particular, unique understanding of the world to bear on unraveling the problems at the end, is for us to decide. I believe that everything from methane to sentience is chemistry, and that we should reexamine our own assumptions concerning the boundaries of our field. Examining the broader assumptions that follow may provide some stimulus to do so.

Indeed, examining the "broader assumptions" of their field in the broadest sense of the term is what chemists should do. The first paragraph presents a fair sampling of the myriad problems in which chemistry can play a central role. They involve everything from engineering interfaces between computers or electronics and human brains to harnessing the power of chemistry in generating, storing, interconverting and deploying energy in all its forms. I strongly think that the future of chemistry lies in recasting itself as an informational science in the broadest sense. At the level of biology chemistry has already manipulated information in the form of sequencing and genomics; synthetic biology will take this capability to a whole new level. But there are other areas in which chemistry can serve to manipulate information, and part of what Whitesides is doing is challenging chemists to become informational scientists in hitherto unexplored areas like energy and transportation.

The essay ends with a systems-level view of chemistry that every chemist should keep in mind, even as she works in her narrow world of natural products, zeolites, ROMP or kinases.

Because chemistry contributes broadly to the foundations of technology, it is particularly difficult to guess its future impact: a new chemical reaction might be used to make a cancer therapeutic, or a chemical weapon. Some of the opportunities that seem within the reach of investigation, if not within the reach of solution—technologies that might substantially prolong life, or develop new forms of life, or lead to sentient systems that rival us in intelligence—will do both good and harm. At minimum, those of us whopursue these problems should accept an obligation to explain to our fellow citizens fully and clearly what we are doing, and why, and (to the limited extent we can) with what possible outcomes. Humankind will do what it will do, but at least everyone should understand—in so far as is possible—what the choices are, and what the consequences might be. Chemistry, if it takes more interest in (and responsibility for) the full scope of programs—from molecules, to applications, and to influence on society—may be able to use the very breadth of its connections to technology to help in this explanation.

Whitesides Image: Boston.com

Splenda and - wait for it - DDT? You've got to be kidding me

noreply@blogger.com (Wavefunction) — Fri, 03 May 2013 03:06:00 +0000

Just when you think the perpetrators of chemophobia (actually this particular case makes chemophobia look like a knight in shining armor) cannot outdo themselves, someone seems to hit a new high.

This time it's "alternative" "medicine" "physician" Joseph Mercola. In a diatribe against Splenda he tosses out this gem:

"Splenda—"Made from Sugar" But More Similar to DDT...

That's right.

The catchy slogan "Made from sugar so it tastes like sugar" has fooled many, but chemically, Splenda is actually more similar to DDT than sugar."

There is no mention of how exactly Splenda is even remotely close to DDT in structure, function or any other conceivable parameter for that matter. I really shouldn't have to do this but here are the structures of the two molecules.

Why in the name of merciful Odin would these be considered similar? Because both of them have chlorines and we all know that chlorine is a toxic gas used in World War 1? I would say then that they share even more hydrogens than chlorines, and hydrogen is of course an inflammable gas, which can only mean that both Splenda and DDT have got to explode when consumed.

Naturally this goes beyond chemophobia and handily ends up way inland in the territory of unadulterated twaddle. Read the entire page if you are craving for that migraine and nausea which you have been longing for. I haven't read the whole thing, and who could blame me for this? A quick look through some of the references reveals the usual egregious howlers (studies extrapolated from rats who have been fed unrealistic doses of the material for an abnormally long period of time etc.) and I have no reason to believe that a more detailed look won't accomplish the same thing.

It strains my imagination to contemplate how even the loopiest of quacks could actually write something like this, let alone sincerely believe it. It's one of those very few times when freedom of speech starts sounding like a bad idea.

H/T: The promising "Chemicals are your Friends" page on Facebook, via Stuart Cantrill.

Stephen Hawking's advice for twenty-first century grads: Embrace complexity

noreply@blogger.com (Wavefunction) — Wed, 24 Apr 2013 20:09:00 +0000

: Charles Joseph Minard's famous graph showing the decreasing size of Napoleon's Grande Armée as it marches to Moscow; a classic in data visualization (Image: Wikipedia Commons)

As the economy continues to chart its own tortuous, uncertain course, there seems to have been a fair amount of much-needed discussion on the kinds of skills new grads should possess. These skills of course have to be driven by market demand. As chemist George Whitesides asks for instance, what's the point of getting a degree in organic synthesis in the United States if most organic synthesis jobs are in China?

Upcoming grads should indeed focus on what sells. But from a bigger standpoint, especially in the sciences, new skill sets are also inevitably driven by the course that science is taking at that point. The correlation is not perfect (since market forces still often trump science) but a few examples make this science-driven demand clear. For instance if you were growing up in the immediate post-WW2 era, getting a degree in physics would have helped. Because of its prestige and glut of government funding, physics was in the middle of one of its most exciting periods. New particles were literally streaming out of woodwork, giant particle accelerators were humming and federal and industrial labs were enthusiastically hiring. If you were graduating in the last twenty years or so, getting a degree in biology would have been useful because the golden age of biology was just entering its most productive years. Similarly, organic chemists enjoyed a remarkably fertile period in the pharmaceutical industry from the 50s through the 80s because new drugs were flowing out of drug companies at a rapid pace and scientists like R. B. Woodward were taking the discipline to new heights.

Demand for new grads is clearly driven by the market, but it also depends on the prevalence of certain scientific disciplines at specific time points. This in turn dictates the skills you should have; a physics-heavy market would need skills in mathematics and electronics for instance, a biology-heavy market would mop up people who can run Western blots and PCR. Based on this trend, what kind of skills and knowledge would best serve graduates in the twenty-first century?

To me the answer partly comes from an unlikely source: Stephen Hawking. A few years ago, Hawking was asked what he thought of the common opinion that the twentieth century was that of biology and the twenty-first century would be that of physics. Hawking replied that in his opinion the twenty-first century would be the "century of complexity". That remark probably holds more useful advice for contemporary students than they realize since it points to at least two skills which are going to be essential for new college grads in the age of complexity: statistics and data visualization.

Let's start with the need for statistics. Many of the most important fields of twenty-first century research including neuroscience, synthetic and systems biology, materials science and energy are inherently composed of multilevel phenomena that proliferate across different levels of complexity. While the reductionist zeitgeist of the twentieth century yielded great dividends, we are now seeing a movement away from strict reductionism toward emergent phenomena. While the word "emergence" is often thrown around as a fashionable place-card, the fact is that complex, emergent phenomena do need a different kind of skill set.

The hallmark of complexity is a glut of data. These days you often hear talk of the analysis of 'Big Data' as an independent field and you hear about the advent of 'data scientists'. Big Data now has started making routine appearances in the pharmaceutical and biotech industry, whether in the form of extensive multidimensional structure-activity relationship (SAR) datasets or as bushels of genomic sequence information. It's also important in any number of diverse fields ranging from voter behavior to homeland security. Statistical analysis is undoubtedly going to be key to analyzing this data. In my own field of molecular modeling, statistical analysis is now considered routine in the analysis of virtual screening hits although it's not as widely used as it should.

Statistics was of course always a useful science but now it's going to be paramount; positions explicitly looking for 'data scientists' for instance specifically ask for a mix of programming skills and statistics. Sadly many formal college requirements still don't include statistics and most scientists, if they do it at all, learn statistics on the job. For thriving in the new age of complexity this scenario has to change. Statistics must now become a mandatory part of science majors. A modest step in this direction is the publication of user-friendly, popular books on statistics like Charles Wheelan's "Naked Statistics" or Nate Silver's "The Signal and the Noise" which have been quickly devoured by science-savvy readers. Some of these are good enough to be prescribed in college courses for statistics non-majors.

Along with statistics, the other important skill for students of complexity is going to be data visualization and formal college courses should also reflect this increasingly important skill set. Complex systems often yield data that's spread over different levels of hierarchy and even different fields. It's quite a challenge to visualize this data well. One resource that's often recommended for data visualization is Edward Tufte's pioneering series of books. Tufte shows us how to present complex data often convoluted by the constrains of Excel spreadsheets. Pioneering developments in human-computer interaction and graphics will nonetheless ease visual access to complicated datasets. Sound data visualization is important not just to simply understand a multilayered system or problem but also to communicate that understanding to non-specialists. The age of complexity will inherently involve researchers from different disciplines working together. And while we are at it it's also important to stress - especially to college grads - the value of being able to harmoniously co-exist with other professionals.

Hawking's century of complexity will call upon all the tools of twentieth century problem solving along with a few more. Statistics and data visualization are going to be at the forefront of the data-driven revolution in complex systems. It's time that college requirements reflected these important paradigms.

First published on the Scientific American Blog Network.

Some thoughts on the events around Boston

noreply@blogger.com (Wavefunction) — Mon, 22 Apr 2013 13:45:00 +0000

We were enjoying a quiet evening of music and reading on Thursday when my wife alerted me to a message she got from the MIT emergency system that there had been a shooting somewhere on the campus. A while later we came to know that a police officer had been shot and killed right in front of my wife's department. After making sure that folks we knew from MIT were safe, we stayed awake for about two more hours reading the news updates. By the time we went to sleep we had found out that there was a connection between the shooting of the MIT police officer - a promising young man who later tragically died - and the Boston marathon bombing.

When we woke up the next day the situation was a little surreal: "Has Boston turned into Baghdad?", a friend tweeted. The police had pursued the two bombing suspects into the neighboring suburb of Watertown where there had been a terrific firefight. One suspect died (died, as it turned out, because his brother ran him over) and his brother escaped. By the time we woke up in Cambridge, Watertown was already in lockdown and police were getting ready for house to house searches within a 20 block perimeter.

Then we heard that Boston and a few of its suburbs - roughly an area comprising a million inhabitants - were in lockdown and all residents had been asked to stay at home. I thought then and I still think that this was an overreaction. Watertown, where the suspect was thought to be hiding? Sure. But Boston, Cambridge, Belmont, Newton and four others? A little over the top in my opinion. I understand that many people stayed home out of deference to authorities' wishes to be able to do their job unfettered. It's also ok to ask residents to be vigilant and to venture out at their own risk, but we do this anyway. Every time we are out we run the risk of being in a traffic accident. I suspect that this risk in a random suburb which is not Watertown is probably higher than a 19 year-old fanatic suffering blood loss coming out of the blue with guns blazing and shooting at you. Now I understand that the police did not force people to stay indoors but they were also quite emphatic about this; I watched a woman who stepped out in the middle of the day to walk her dog being emphatically told to stay inside by two officers out on patrol.

The huge police presence in Watertown also seemed like an overreaction to me. By one account there were 9000 local, state, and federal authorities looking for this kid. Armored vehicles patrolled the streets, and I am not sure what additional purpose they would have served. Sure, the authorities were erring on the side of safety and they were clearly anxious to apprehend the suspect as soon as possible, but I think it's constitutionally healthy to be skeptical when your whole neighborhood resembles a war zone and armed officers wielding every kind of weapon perform intrusive house searches.

For me the ultimate irony may be that this guy was located - not by one of the 9000 officers and military personnel - but by an ordinary citizen. In a boat in an area that was not part of the 20 block perimeter. After the lockdown order had been rescinded.

What happened there? I know that hindsight is always twenty-twenty but here's something that bothers me: From what I read it seems that the spectacular shootout occurred at the intersection of Laurel St and Dexter Ave in Watertown. The suspect was found hiding in the boat at 67 Franklin St. If you look at these locations on Google Maps they are less than a mile apart. For all the meticulous house-to-house searches and lockdowns, why did the perimeter not include a location that was less than a mile from where the shootout took place? And most importantly, how could the police miss the boat, a large, roomy object that's ideal for a human being to hide? Can you say that your operation was really successful when an ordinary citizen locates a suspect only after you are done with house-to-house searches? So on one hand there seemed to be an overreaction and on the other, the meticulous operation seems to have been unsuccessful in its primary purpose.

I understand that there were a lot of police officers and other personnel who immersed themselves into this investigation. Many of them had not slept in 24 hours and they were clearly committed to finding this guy as soon as possible. These people clearly did an admirable job and we should applaud their dedication. But in my opinion there seem to be a few important clues that were missed, and discussing these clues is not only an important part of a healthy democracy where public officials are answerable to the public but also a part of any system of self-improvement and feedback where you learn from your mistakes. Most importantly though, when a 19 year-old nutjob brings a major American city to a standstill, makes it resemble a state with martial law and makes people stay put in their houses and away from their jobs in anxiety, if not fear, the terrorists have already won (as the cliche goes, in this case because it's true). As Ben Franklin memorably put it, if you sacrifice freedom for security you risk losing both. And the key here is to realize that this sacrifice may not even be forced upon you by the state; it can be entirely self-imposed.

At 5 PM I grew really restless and decided to go outside to get some milk (I need my morning coffee fix, terrorist scares be damned). Everything except for one convenience store was closed. Parking on Massachusetts Ave never looked better. The next day we went to the Esplanade along the Charles River. The cherry blossoms were in full bloom. Something about fear being the only thing we should truly fear came to my mind.

Moore's Law for batteries: No dice

noreply@blogger.com (Wavefunction) — Wed, 10 Apr 2013 13:27:00 +0000

: The REVAi/G-Wiz i electric car charging at an on-street station in London (Image: Wikipedia Commons)

Ever since Gordon Moore came up with the ubiquitous law bearing his name, it has been applied to paradigms far beyond those which it was intended for. This is perhaps not surprising; the history of science and technology - and of religion - has consistently demonstrated that the followers of a prophet usually extend his principles into domains which the prophet never really approved of.

Transistor technology does neatly seem to follow the Moore's Law curve and a few other cutting-edge technologies like genome sequencing also seem to do this. Yet Moore's proselytizers have extended his law to pretty much everything. The law especially seems to break down when applied to biomedical research; for instance a review from last year pointed out how the pace of drug development almost seems to have been following a reverse law, titled "Eroom's Law" of declining productivity. Kurzweilian prognostications notwithstanding, research in neuroscience might follow the same trajectory, with a burst of rapid mapping of neuronal connectivity followed by a long, fallow period in which we struggle to duplicate these processes by artificial means.

The basic reasons why an emerging technology may not follow Moore's Law is either because we tend to underestimate the complexity of the system to which the technology is applied, or we underestimate the basic principles of physics and chemistry which would inherently constrain a Moore-type breakthrough in that field. In case of medical research both these constraints seem to rear their ugly, emergent heads, and this is the main problem I have with futurists like Ray Kurzweil who seem to imagine an entire universe governed by Moore's Law-type exponential progress in every field. Not all levels of complexity are created equal, and we just don't have enough evidence to know how general Moore's Law (which I think should simply be re-named "Moore's Observation") is in the world of practical problem-solving.

The argument about basic science limitations may especially apply to much-touted battery research whose proponents often seem to declare the next breakthrough in battery technology as being just around the corner. But a perspective from Fred Schlachter from the American Physical Society in the Proceedings of the National Academy of Sciences puts a brake on these optimistic predictions. His point is simple: any kind of Moore's Law for batteries may be limited by the fundamental chemistry inherent in a battery's workings. This is unlike transistors, where finer lithography techniques have essentially enabled a repetitive application of miniaturization over the years.

There is no Moore’s Law for batteries. The reason there is a Moore’s Law for computer processors is that electrons are small and they do not take up space on a chip. Chip performance is limited by the lithography technology used to fabricate the chips; as lithography improves ever smaller features can be made on processors. Batteries are not like this. Ions, which transfer charge in batteries are large, and they take up space, as do anodes, cathodes, and electrolytes. A D-cell battery stores more energy than an AA-cell. Potentials in a battery are dictated by the relevant chemical reactions, thus limiting eventual battery performance. Significant improvement in battery capacity can only be made by changing to a different chemistry.

And even this different chemistry is going to be governed by fundamental parameters like the sizes of ions and the rates of chemical reactions and current flow. Schlachter goes on to note the problems that lithium batteries have recently encountered, including fires. There is thus no guarantee that there will be a breakthrough in battery technology that's equivalent to that in computer technology over the last thirty years. And the article is right that while we are waiting for such breakthroughs, it's a really good idea to push forward with improving energy efficiency in cars, making their lighter, smaller and and more powerful. Energy efficiency would not ultimately solve pollution problems since the cars would still be fueled by gasoline, but it would certainly take us a long way while we are waiting for the next battery breakthrough engineered by Moore's Law. A law which may not really hold when it comes to next generation electric technology.

First published on the Scientific American Blog Network.

Friday levity: 'Nature' discusses ghosts.

noreply@blogger.com (Wavefunction) — Fri, 29 Mar 2013 18:22:00 +0000

One of the pleasures of thumbing through old issues of science journals is the opportunity to accidentally discover articles or letters that make you do double takes, often followed by face palms.

As I was about to read a letter in Nature bemoaning the closure of the Hoffmann-La Roche Institute of Molecular Biology in Nutley, NJ (Nature, 1995, 373, 184; deja vu, anyone?) I came across a letter on the same page that pristinely tosses out the following for readers' benefit (click for clarity...or the lack thereof).

I love the fact that the letter writer dismisses one hypothesis about ghosts only to come up with another. And this isn't 1885, it's 1995. Oh how I miss the old Nature.

Chemical compounds from mouthwash may target cancer cells

noreply@blogger.com (Wavefunction) — Wed, 27 Mar 2013 01:18:00 +0000

Apoptosis or programmed cell death is one of the great truths of cellular life, an essential process that’s not only required to make way for new cells but to prevent old cells from going haywire. When cells circumvent this great truth they start dividing uncontrollably and contribute to cancer. Our knowledge of cancer over the last three decades has confirmed the central role that a breakdown in the usual mechanisms of apoptosis plays in pushing a cell across the tipping point into a cancerous state. Of the many strategies to fight cancer, one consists of trying to find drugs that force cells to regain their normal balance of apoptosis. Now this effort may have found an unlikely ally.

Chlorhexidine is an antibacterial and plaque-fighting compound that is a common component of mouthwash, usually present as a 0.1% or 0.2% solution. In a paperpublished in the journal Angewandte Chemie, scientists in Germany report an unexpected effect of chlorhexidine and its related cousin alexidine: they inhibit cancer cells in the mouth by blocking an important protein-protein interaction. This research opens up new directions in investigating this class of compounds as anticancer agents and also sheds light on the value of finding novel potential uses for everyday chemical compounds. One of the great advantages in this endeavor is that the “repurposed” compounds have already run the gauntlet of safety tests required by the FDA, potentially shortening the period of approval for their new uses.

Protein-protein interactions (PPIs) are often considered the next frontier in drug discovery. They are involved in almost every important molecular-level event in health and disease. Traditional drugs work by blocking the action of single proteins (typically fitting into them like a key fits into a lock) but since there are many more protein-protein interactions than single proteins, there is enormous potential in developing drugs that disrupt these interactions, many of which are upregulated in diseases like cancer. Unfortunately targeting PPIs is difficult because of a variety of reasons; they have large, spread-out interfaces which makes it difficult for small organic molecules to span their surface area, and typically the ones which do are too big to satisfy the many qualities of an ideal drug, such as an ability to get inside cells in the first place.

One of the most well studied PPIs is the interaction between a family of pro-apoptotic and anti-apoptotic proteins called the Bcl-2 family. These proteins are present in all our cells. As their name indicates, one group of proteins speeds up apoptosis while the other group inhibits it. In a normal cell there is a usually a precise balance between these two activities engineered by the two sets of proteins binding to each other and regulating each other’s function. It’s a delicate dance which ensures that the cells are active only when needed and any cells gone haywire are eliminated. In cancer this precise balance is disrupted and the anti-apoptotic proteins are over-expressed and become dominant. One anti-apoptotic protein named Bcl-Xl in particular keeps its usually equipotent pro-apoptotic protein partner named Bak bound up and prevents the cell from committing suicide; this molecular-level feud leads to uncontrolled cell division. Over the years researchers have tried to find many druglike molecules and peptides which could block Bcl-Xl and free up the Bak protein. But none of the attempts have resulted in a clinically marketed drug.

What the researchers in Germany did was to screen about 4000 everyday chemical compounds to look for ones that might block the Bcl-Xl protein. They found two which, surprisingly, had very different uses. Chlorhexidine and alexidine are common components of mouthwash. Both compounds were found to inhibit the Bcl-Xl – Bak interaction at a concentration that’s much lower than that found in mouthwash. Surface-exposed oral cells in the mouth are thus bathed in a rather potent concentration of small molecules that prevent at least one important mechanism involved in cancer from manifesting itself. The researchers also did further experiments, including computer modeling, that localized the site of binding of the two compounds on the Bcl-Xl protein. This site was the same as that occupied by the Bak protein, further supporting the blocking interaction of the mouthwash components with the anti-apoptotic protein.

Finally the researchers tested these two compounds against cancerous cells from the tongue and the pharynx. Both compounds were found to significantly reduce the degree of apoptosis suppression in these cells, connecting the molecular level interaction of the molecules to actual anticancer effects.

This study is interesting for several reasons. It directly leads to a new class of compounds that may have promising anticancer activities; very likely the compounds’ structures would have to be modified by chemists to improve their properties, but this is what chemists have always done best. The therapeutic concentration that’s required for inhibiting the proteins is already exceeded in your garden variety mouthwash; this may also indicate a healthy margin of safety. A more intriguing question to ask is whether the use of mouthwash correlates with lower incidence of oral cancer. The literature on the relationship between mouthwash and oral cancer has been confusing and there don’t seem to be large-scale studies investigating a possible connection. By suggesting a possible mechanism of cancer prevention, this study provides a strong motivation to gather epidemiological data about possible anticancer effects of mouthwash and its components. It’s too early to start dousing your mouth with mouthwash though since these compounds only target one kind of interaction and we don’t have enough data on higher concentrations and long-term effects. But it’s definitely a promising start that points the way to interesting experiments, and that’s what science is best at doing.

Most tantalizingly though, the study asks what other kinds of therapeutic effects may be hidden in everyday chemical products, in our bathroom and kitchen closets. Nature is much more interesting than we think and molecules often lead double lives. Contemplate this the next time you brush your teeth or wash your dishes.

First published on the Scientific American Blog Network.

Solomon Snyder on academic publishing: ask for adequate, not exhaustive, documentation

noreply@blogger.com (Wavefunction) — Thu, 07 Mar 2013 16:41:00 +0000

Image: Corpus Callosum

Renowned neuropharmacologist Solomon Snyder has a thought-provoking take on what seems to be one of the two evils that has plagued modern academia: publication (the other one is the job market). I have previously blogged about the increasing conservatism of academic publishing myself, and in this case “conservatism” also translates to “excessive rigor”.

Snyder starts by lamenting the startling fact that the average duration for a modern American biomedical scientist to start his or her academic career is about the same as that for a neuro or cardiovascular surgeon, people whose specialty is usually considered to be in the top tier of their profession; the difference of course is that a cardiovascular surgeon starts making $500K right off the bat while a new assistant professor starts making $80K and almost never goes beyond $200k or so. The long trudge begins with graduate education, the average duration of which has stretched out over the last three decades (these days, a 5 year Ph.D. is considered relatively quick). Every part of the academic process, from getting a postdoctoral position to your first job to your first grant, has turned into a war of attrition. The “winners” who emerge at the end of it are often demoralized academics in their early 40s whose best years may be behind them. And the situation seems to only be getting worse.

But the article’s really about publishing papers. Snyder hits the nail when he says that academic publishing has become so rigorous in asking for exhaustive experimentation and documentation that it dissuades many authors from publishing their best ideas, ideas which are interesting and valid but which may not have been completely fleshed out. He points to reviewers’ insistence that authors perform a comprehensive set of experiments – often ranging over several months – that would qualify their manuscript for publication. Anyone who has tried to publish biomedical papers must be well aware of how tedious and demoralizing the experience can be. This long-drawn process significantly impacts the progress of science:

“Why does it take so much longer to move from test tube to the printed page? One element is a journal review process that is substantially lengthier, especially in terms of experiments required to address the concerns of referees. To anticipate such referee responses, scientists preemptively carry forward experimentation more exhaustively than is necessary to document their assertions. Yet, we can clone genes in a couple of days. Shouldn’t we be able to complete experiments to satisfy reviewers in a few weeks rather than the 7–12 months typically consumed in revision, not to mention the many years devoted to developing the original manuscript? If one spends 5 years accumulating the data for a manuscript and another year revising it to satisfy referees, benefits to the public are delayed for years.”

In contrast Snyder points to his postdoctoral advisor, another legendary scientist named Julius Axelrod at the NIH who churned out discovery after discovery in short order and won a Nobel Prize (the Axelrod dynasty is nicely charted out in Robert Kanigel’s book “Apprentice to Genius”). The point that Snyder is making is that in those days the reviewing process was much quicker but the quality of science doesn’t seem to have suffered in spite of this speedier turnaround. What has gone wrong since then?

Snyder partially places the blame at the feet of Cell founder Benjamin Lewin who wanted Cell to showcase papers that were essentially complete stories; from hypotheses to final products. But Lewin also made the process highly streamlined. Reviewers were warned to stay away from insults, stick to succinct criticism and suggest adequate but not unrealistic experiments and further studies. The objective was to get the best science out in a form that was interesting enough to spark further inquiry but which was not necessarily the last word.

Lewin understood the piecemeal nature of science where researchers build on each other’s discoveries. This understanding of the scientific process has since been subverted by academic reviewers, partially to cull a flood of proposals and ideas and partially to satisfy their own whims. Sometimes old boys’ networks can conspire to put sound science in a straitjacket. Expecting every research project to tell complete, final stories not only imposes unrealistic and demotivating standards on scientists but also ignores the always incomplete and provisional nature of science. Snyder asks that expectations for accepting papers be changed and points to recent developments like the journal eLIFE which incorporates some of his thinking. Blogger SciCurious suggests her own system of peer-review where a paper is simultaneously sent to a group of journals with different standards; after hearing back from reviewers, the authors can decide whether to push ahead with further experiments to satisfy the top-tier journals or whether to publish the paper in a lower-tier journal right away. But Snyder’s perspective points out that all journals – whether top tier or otherwise – should have a reviewing system that allows for rapid dissemination of results.

Reviews and authors need to seriously contemplate Snyder’s recommendations. Academic research has already turned into a long slog with its uncertain job market and draconian grant approval and does not to face need additional difficulties in the form of glacial and unrealistic reviewing standards. Let’s remember that the purpose of science is to generate ideas, not products. And it shouldn’t take very long for ideas to see the light of day.

First published on Scientific American Blogs.

First they came for the bloggers and I didn't speak up because...

noreply@blogger.com (Wavefunction) — Tue, 05 Mar 2013 13:09:00 +0000

Here's a breath of fresh air. I keep on thinking about Planck's quote about scientific revolutions not occurring until old generations die and new ones take their place and here's something of that sort happening, even if in a minor way.

Prof. Phil Baran has started his own blog. It's easy to see this as a response to the commendable IBX oxidation experiment carried out by Blog Syn. That, by the way, was a great illustration of how science should work; research is published, it is then scrutinized, a few discrepancies are found, the original author responds and confirms the original results, and the new authors discover something new that had not been realized before.

But it's clear that the Blog Syn incident was only a seed for a realization that undoubtedly must have been crystallized in Phil's mind for a while. We have all seen how the old guard has often dismissed and scorned bloggers and their pesky, amateur blogs. Now here's someone from the new guard who clearly recognizes which way the winds are blowing:

Over the years I have vaguely followed some of them, mostly through my students or through being occasionally contacted by someone that runs a blog. Practically all of my colleagues roll their eyes the minute the word "blog" is uttered for a variety of largely justified reasons.

But times are clearly changing...Last year I was at a dinner symposium where EJ Corey gave a brilliant impromptu talk before a toast. It was a captivating speech all about how things have rapidly changed over the span of his 80+ years. The take home message was that change is natural and you can either embrace it and adapt or be left behind. I'm no fortune teller but it is clear to me that blogging is here to stay and is gathering momentum.

There is something ironic about the fact that the words of the great E. J. Corey - an exemplar of the old guard who almost certainly is not going to start blogging anytime soon - should serve as an invitation to blog for the man who is widely regarded as one of the most creative synthetic organic chemists of his generation.

Thank you Prof. Baran. Now, the next time they come for us, we know you will speak up because you are are a blogger.

Other reactions: Chembark

ENCODE, Apple Maps and function: Why definitions matter

noreply@blogger.com (Wavefunction) — Thu, 28 Feb 2013 17:10:00 +0000

: ENCODE (Image: Discover Blogs)

Remember that news-making ENCODE study with its claims that “80% of the genome is functional”? Remember how those claims were the starting point for a public relations disaster which pronounced (for the umpteenth time) the "death of junk DNA"? Even mainstream journalists bought into this misleading claim. I wrote a post on ENCODE where I expressed surprise at why anyone would be surprised by junk DNA to begin with.

Now Dan Graur and his co-workers from the University of Houston have published a meticulous critique of the entire set of interpretations from ENCODE. Actually let me rephrase that. Dan Graur and his co-workers have published a devastating takedown of ENCODE in which they pick apart ENCODE’s claims with the tenacity and aplomb of a vulture picking apart a wildebeest carcass. Anyone who is interested in ENCODE should read this paper, and it’s thankfully free.

First let me comment a bit on the style of the paper which is slightly different from that in your garden variety sleep-inducing technical article. The title – On the Immortality of Television Sets: Function in the Human Genome According to the Evolution-Free Gospel of ENCODE – makes it clear that the authors are pulling no punches, and this impression carries over into the rest of the article. The language in the paper is peppered with targeted sarcasm, digs at Apple (the ENCODE results are compared to AppleMaps), a paean to Robert Ludlum and an appeal to an ENCODE scientist to play the protagonist in a movie named "The Encode Incongruity". And we are just getting warmed up here. The authors spare little expense in telling us what they think about ENCODE, often using colorful language. Let me just say that if half of all papers were this entertainingly written, the scientific literature would be so much more accessible to the general public.

On to the content now. The gist of the article is to pick apart the extremely liberal, misleading and scarcely useful definition of “functional” that the ENCODE group has used. The paper starts by pointing out the distinction between function that’s selected for and function that’s merely causal. The former definition is evolutionary (in terms of conferring a useful survival advantage) while the latter is not. As a useful illustration, the function of the human heart that is selected for is to pump blood while the function that’s causal is an additional weight of 300 grams and a capacity for producing thumping sounds.

The problem with the ENCODE data is that it features causal functions, not selected ones. Thus for instance, ENCODE assigns function to any DNA sequence that displays a reproducible signature like binding to a transcription factor protein. As this paper points out, this definition is just too liberal and often flawed. For instance a DNA sequence may bind to a transcription factor without inducing transcription. In fact the paper asks why the study singled out transcription as a function: “But, what about DNA polymerase and DNA replication? Why make a big fuss about 74.7% of the genome that is transcribed, and yet ignore the fact that 100% of the genome takes part in a strikingly “reproducible biochemical signature” – it replicates!”

Indeed, one of the major problems with the ENCODE study seems to be its emphasis on transcription as a central determinant of “function”. This is problematic, since as the authors note, there's lots of sequences that are transcribed which are known to have no function. But before we move on to this, it’s worth highlighting what the authors call “The Encode Incongruity” in homage to Robert Ludlum. The Encode Incongruity points to an important assumption in the study; the implication that a biological function can be maintained without selection and that the sequences with “causal function” identified by ENCODE will not accumulate deleterious mutations. This assumption is unjustified.

The paper then revisits the five central criteria used by ENCODE to define “function” and carefully takes them apart:

1. “Function” as transcription.

This is perhaps the biggest bee in the bonnet. First of all, it seems that ENCODE used pluripotent stem cells and cancer cells for its core studies. The problem with these cells is that they display a much higher level of transcription than other cells, so any deduction of function from transcription in these cells would be exaggerated to begin with. But more importantly as the article explains, we already know that there are three classes of sequences that are transcribed without function; introns, pseudogenes and mobile elements (“jumping genes”). Pseudogenes are an especially interesting example since they are known to be inactive copies of protein-coding genes that have been rendered dead by mutation. Over the past few years as experiments and computational algorithms have annotated more and more genes, the number of pseudogenes has gone up even as the number of protein-coding genes has gone down. We also know that pseudogenes can be transcribed and even translated in some cells, especially of the kind used in ENCODE, just as we know that they are non-functional by definition. Similar arguments apply to introns and mobile elements, and the article cites papers which demonstrate that knocking these genes out doesn't impair function. So why would any study label these three classes of sequences as functional just because they are transcribed? This seems to be a central flaw in ENCODE.

A related point made by the authors is statistical in which they say that the ENCODE project has sacrificed selectivity for sensitivity. There are some simple numerical arguments that point to the large number of false positives inherent in sacrificing selectivity for sensitivity. In fact this is a criticism that goes to the heart of the whole purpose of the ENCODE study:

“At this point, we must ask ourselves, what is the aim of ENCODE: Is it to identify every possible functional element at the expense of increasing the number of elements that are falsely identified as functional? Or is it to create a list of functional elements that is as free of false positives as possible. If the former, then sensitivity should be favored over selectivity; if the latter then selectivity should be favored over sensitivity. ENCODE chose to bias its results by excessively favoring sensitivity over specificity. In fact, they could have saved millions of dollars and many thousands of research hours by ignoring selectivity altogether, and proclaiming a priori that 100% of the genome is functional. Not one functional element would have been missed by using this procedure.”

2. “Function” as histone modification

Histones are proteins that pack DNA into chromatin. The histones then undergo certain chemical modifications called post-translational modifications that cause the DNA to unpack and be expressed. ENCODE used the presence of 12 histone modifications as evidence of “function”. This paper cites a study that found a very small proportion of possible histone modifications associated with function. Personally I think this is an evolving area of research but I too question the assumption of having a function associated with most histone modifications.

3. “Function” as proximity to regions of open chromatin

In contrast to histone-packaged DNA, open chromatin regions are not bound by histones. ENCODE found that 80% of transcription sites were within open chromatin regions. But then they seem to have committed the classic logical fallacy of inferring the opposite, that most open chromatin regions are functional transcription sites (there’s that association between transcription and function again). As the authors note, only 30% or so of open chromatin sites are even in the neighborhood of transcription sites, so associating most open chromatin sites with transcription seems to be a big leap to say the least.

4. “Function” as transcription-factor binding.

This to me is another huge assumption inherent in the ENCODE study, especially as a chemist. As I mentioned in my earlier post, there are regions of DNA that might bind transcription factors (TFs) just by chance through a few weak chemical interactions. The binding might be extremely weak and may be a quick association-dissociation event. To me it seemed that in associating any kind of transcription-factor binding with function, the ENCODE team had inferred biology from chemistry. The current analysis gives voice to my suspicions. As the authors say, transcription sites are usually very short which means that TF-binding “look-alikes” may arise in a large genome purely by chance. Any binding to these sites may be confused with real TF-binding sites. The authors also cite a study in which only 86% of TF-binding sites in a small sample of 14 sites showed experimental binding to a TF. Extrapolating to the entire genome, it could mean that a fraction of the conjectured TF-binding sites may actually bind TFs.

5. “Function” as DNA methylation.

This is another instance in which it seems to me that biology is being inferred from chemistry. DNA methylation is one of the dominant mechanisms of epigenetics. But by itself DNA methylation is only a chemical reaction. The ENCODE team built on a finding that negatively correlated gene expression with methylation in CpG (cytosine-guanine) sites. Based on this they concluded that 96% of all CpGs in the genome are methylated, and therefore functional. But again, in the absence of explicit experimental verification, CpG methylation cannot be equated with gene expression. At the very least this indicates follow-up work which will need to confirm the relationship. Until then the hypothesis that CpG methylation implies function will have to remain a hypothesis.

So what do we make of all this? It’s clear that many of the conclusions from ENCODE have been extrapolations devoid of hard evidence.

But the real fly in the ointment is the idea of “junk DNA” which seems to have evoked rather extreme opinions that have ranged from proclaiming junk DNA as extinct to proclaiming it as God. Both these opinions perform a great disservice to the true nature of the genome. The former reaction virtually rolls the red carpet for “designer” creationists who can now enthusiastically remind us of how each and every base pair in the genome has been lovingly designed. At the same time, asserting that junk DNA must be God is tantamount to declaring that every piece of currently designated junk DNA must forever be non-functional. While the former transgression is much worse, it’s important to amend the latter belief. To do this the authors remind us of a distinction made by Sydney Brenner between “junk DNA” and “garbage DNA”. There’s the rubbish we keep and the rubbish we discard, but some rubbish may potentially turn useful in the future. At the same time, rubbish that may be useful in the future is not rubbish that’s useful in the present. Just because some “junk DNA” may turn out to have a function in the future does not mean most junk DNA will be functional. In fact as I mentioned in my post, the presence of large swathes of non-functional DNA in our genomes is perfectly consistent with standard evolutionary arguments.

The paper ends with an interesting discussion about “small” and “big” science that may explain some of the errors in the ENCODE study. The authors point out that big science has generally been in the business of generating and delivering data in an easy-to-access format. Small science has been much more competent in then interpreting the data. This does not mean that scientists working on big science are incapable of data interpretation; what it means is that the very nature of big data (and the time and resource allocation inherent in it) may make it very difficult for these scientists to launch the kinds of targeted projects that would do the job of careful data interpretation. Perhaps, the paper suggests, ENCODE’s mistake was in trying to act as both the deliverer and the interpreter of data. In the authors’ considered opinion, ENCODE “tried to perform a kind of textual hermeneutics on the 3.5 billion base-pair genome, disregarded the rules of scientific interpretation and adopted a position of theological hermeneutics, whereby every letter in a text is assumed a priori to have a meaning”. In other words, ENCODE seems to have succumbed to an unfortunate case of ubiquitous pattern seeking from which humans often suffer.

In any case, there are valuable lessons in this whole episode. The mountains of misleading publicity it generated, even in journals like Science and Nature, were a textbook study in media hype. As the authors say:

“The ENCODE results were predicted by one of its lead authors to necessitate the rewriting of textbooks (Pennisi 2012). We agree, many textbooks dealing with marketing, mass-media hype, and public relations may well have to be rewritten.”

From a scientific viewpoint, the biggest lesson here may be to always keep fundamental evolutionary principles in mind when interpreting large amounts of noisy biological data under controlled laboratory conditions. It’s worth remembering the last line of the paper:

“Evolutionary conservation may be frustratingly silent on the nature of the functions it highlights, but progress in understanding the functional significance of DNA sequences can only be achieved by not ignoring evolutionary principles…Those involved in Big Science will do well to remember the depressingly true popular maxim: “If it is too good to be true, it is too good to be true.”

The authors compare ENCODE to AppleMaps, the direction-finding app in the iPhone that notoriously bombed when it came out. Yet AppleMaps also provides a useful metaphor. Software can evolve into a useful state. Hopefully, so will our understanding of the genome.

First published on the Scientific American Blog Network.

Uncle Syd's idea for funding new assistant professors

noreply@blogger.com (Wavefunction) — Wed, 20 Feb 2013 19:56:00 +0000

I was leafing (virtually of course) through old issues of "Current Biology" when I came across a thought-provoking, slightly tongue-in-cheek essay by Sydney Brenner in an issue from 1994. Brenner used to write a regular column for the magazine and his thoughts ranged from improving lab conditions to junk DNA; as is characteristic of Brenner's incisive mind, almost all the columns give you something new to think about.

It was Brenner's ("Uncle Syd") fictitious letter to an assistant professor ("Dear Willie") just starting out in his new career that caught my eye. Perhaps the column can offer some ideas to assistant professors floundering in this gloomy age of funding crunches and declining job prospects. After acknowledging the fundamental and paradoxical difficulty that new professors who need funding the most don't have any experience in getting it, Brenner comes up with a framework - the BISCUIT:

"I have for long entertained an elegant solution to this difficulty, and that is to found a bank, BISCUIT (Bank of International Scientific Capital and Unpublished Information and Techniques), that will lend scientific capital to first-time grant applicants and others in need. It will not only lend ideas for research but also loan experiments that have been carried out but have not been published. We have to be careful with the latter, because although such holdings are of high value they could undergo instant depreciation if someone else does the experiment and publishes the result. Where, you ask, does the bank get its capital? No problem. I know a number ofscientists who have a surplus of scientific ideas and lots of experiments that they find too boring to write up and these 'wealthy' individuals would be the first investors. The bank would also continue to receive deposits. Once we got going, everything would be fine, because the borrowers would not only have to pay back capital but we would charge interest so that our holdings grew. And, of course, if any depositor were to suffer a catastrophic career collapse, he could withdraw all of his capital and start again. The beauty of it is that he would get new, up-to-date ideas and experiments and, in this way, his original deposit, although used a long time ago, will have retained its value and will not have been corroded by time. I am amazed that in these times ofhigh-powered service industries nobody has thought of doing this before, but perhaps that's because it is only scientists who will profit from the BISCUIT bank."

Reference: Current Biology, 1994, 4, 10, 956

On toxic couches and carcinogens: Chemophobia, deconstructed.

noreply@blogger.com (Wavefunction) — Mon, 11 Feb 2013 20:03:00 +0000

Last week I attended a great session on chemophobia at ScienceOnline 2013 headed by Carmen Drahl and Dr. Rubidium. The session emphasized how "trigger words" - alarmist phrases judiciously placed in the middle of otherwise well-intentioned paragraphs - can make people believe that something is more serious than it is. The session also reinforced the all-important point that context makes all the difference when it comes to chemistry.

Sadly I could not read a recent post about flame retardants in couches on the Scientific American Guest Blog without remembering some of these caveats. The post unfortunately seems to me to present a first-rate example of how well-intentioned opinion and advice can nonetheless be couched in alarmism and assertions drawn out of context. It evidences lapses that are common in chemophobic reporting. Let me state upfront that my argument is as much about the tone and message of the post as it is with the pros and cons of the scientific evidence (although there's some highly questionable scientific conclusions in there). Some of my analysis might look like nitpicking, but the devil is often in the details.

The article is written by Sarah Janssen, an M.D. Ph.D. who is worried about supposedly "toxic chemicals" in her couch. In this case the chemical turns out to be something called Chlorinated Tris. Dr. Janssen is apparently so worried that she has already decided that her family should sit on the floor/carpet or eat at the table than be exposed to the couch. At the end of the post she says that she will look forward to the time when she can buy a "toxic-free couch".

The trigger words start coming at you pretty much right away:

"A nationwide study of 102 couches revealed that my couch, among others tested, contains OVER A POUND of chlorinated Tris, a cancer-causing chemical removed from children’s pajamas in the 1970s and now listed on California’s Proposition 65 list of carcinogens"

Observe how ONE POUND is capitalized, as if the capitalization makes any additional arguments in favor of the compound's toxicity superfluous. But we all know that the dose depends on the context; there's more than one pound of lots of chemical substances in almost every piece of furniture that I use, but the weight by itself hardly makes the material harmful. In fact since the weight of a typical couch is at least 20 pounds, I wouldn't expect to find any less than one pound of a flame-retardant substance in it. The point is that simple manipulations like capitalization enhance the public's perception of impact, and doing this without a good reason sends the wrong message.

Now let's look at the chemical itself, Chlorinated Tris, or TRIS(1,3-DICHLORO-2-PROPYL) PHOSPHATE (TDCPP) in chemical parlance (there, did the capitalization make it sound more sinister?). Googling this chemical turns up a bunch of newspaper articles without primary references. How about a more formal source, in this case a June 2011 report by the California EPA? Scientifically inclined readers will find lots of interesting data in there and it's clear that chlorinated tris has a variety of observable and potentially concerning effects on cells. But for me the most important part of the report talked about a study on the effects of TDCPP on cancer risk in a group of 289 workers at a TDCPP plant between 1956 to 1980. The operative line in that paragraph is the following:

"The authors concluded that although the SMR (standard mortality rate) from lung cancer was higher than expected, overall there was no evidence linking the lung cancers to TDCPP exposure because all three cases with lung cancer were heavy to moderate cigarette smokers. Small sample size and the inability to account for confounding factors make it difficult to draw conclusions from this study."

In addition the paragraph states that p-values (a measure of statistical significance) could not be calculated because of small sample size. Now this study was done with people who have literally lived and breathed in a TDCPP-rich environment for almost thirty years. If anyone should suffer the ill-effects of TDCPP it should probably be this group. And still the conclusions were dubious at best, so one wonders if merely sitting on a couch would do anything at all.

As is usually the case, the report has much more information about the effects of TDCPP in mice and here you do see evidence of tumor formation. But the sample sizes are again small. More importantly, what's the dosage of TDCPP that causes statistically significant cancers to appear in mice? It's 80 mg per kilogram per day. This would translate to 5.6 grams per day for a 70-kg human being. And although I haven't read all the original studies with mice, I am assuming that this amount would have to be ingested, inhaled or injected. So no, unless you are out of supplies in a nuclear holocaust and are forced to survive by actually eating the foam from your couch, you would most likely not get cancer from simply sitting on a couch with TDCPP in it. And even this tenuous conclusion comes from studies with mice; as indicated above, the data is far from clear for humans. In fact I would guess that the probability of suffering an obesity-induced heart attack from sitting for long periods on a couch exceeds the probability of getting cancer from TDCPP.

Now that doesn't mean that I am claiming that TDCPP has no harmful effects in humans. But it's clear that at the very least we need to get much more rigorous data to establish a causal relationship with any kind of confidence. For now the evidence just doesn't seem to be there. Claiming that simply sitting on a TDCPP-filled couch could cause cancer, with any kind of probability, is really no more than a theory disconnected from data.

It gets worse. The post later talks about the smoke from fire retardant-containing furniture "putting firefighters' health at greater risk of cancer". When you click on that link it takes you to an article in the San Francisco Chronicle documenting the story of a firefighter named Stefani who is a cancer survivor. The firefighter had expressed concerns about his cancer being linked to smoke inhalation from household items like furniture. But here's what the article itself says at one point:

"The relationship between Stefani's job and transitional cell carcinoma is less clear...there's no hard evidence yet that chemicals contribute to this condition, said Dr. Kirsten Greene, a UCSF assistant urology professor who helped run the study."

When an expert who ran the study questions the link between cancer and flame retardants, it should give you pause for thought (on a related note, kudos to the SFC for reporting the skepticism).

Finally, there's no better way to drive home the pernicious influence of "chemicals" than to demonstrate their existence in the bodies of every species on the planet:

"But flame retardants aren’t just polluting our homes—they are polluting the world, literally. During manufacturing, use and disposal, these chemicals are released into the environment where they can be found in air, water, and wildlife. Birds, fish, mammals including whales and dolphins and animals living far from sources of exposure, such as polar bears in the Arctic, have been found to have flame retardants in their bodies."

But take a look at the polar bears paper. Notice that we have now switched from TDCPP to brominated flame retardants, a different category of compound. If there's anything chemists know, it's the fact that function follows structure; no chemist would assume that TDCPP and brominated ethers would have the same effects without explicit evidence. The subsequent paragraph describing a variety of other non-carcinogenic effects also talks about brominated compounds. The continuity in the article would have you believe that we are still talking about TDCPP and couches. More importantly though, chemical substances are not all toxic just because they show up in multiple species, and bioaccumulation does not automatically translate into carcinogenicity (as is clear from the polar bear study). Since the advent of human civilization there have been thousands of synthetic molecules that have been dispersed in the environment, and the vast majority of them co-exist in peace with other species. But the most important point here is that it's extremely hard to extrapolate these studies to the conclusion that sitting on your couch may expose you to a carcinogen; that kind of extrapolation pretty much ignores dose, context, statistical significance and species-specific differences and lumps all "flame retardants" into the same category without allowing for compound-specific effects.

Trigger words proliferate the rest of the post: "dangerous chemicals", "harmful chemical substances", "toxic-free couch"...the list goes on. I don't want it to sound like I am picking on this particular post or author; sadly this kind of context-free alarmism is all too common in our chemophobic culture. But articles like this keep on making one thing clear: the details matter. You really cannot write a report like this without looking into details like statistics, nature of test organisms, dosage, method of administration, controls, sample size and species-specific differences. Lack of attention to these details is often a common hallmark of articles propagating chemophobia. If you ignore these details you are not really reporting science, you are simply reporting a gut feeling. And gut feelings are not exactly good metrics for making policy decisions.

Chemistry Nobel Prizes and second acts

noreply@blogger.com (Wavefunction) — Thu, 07 Feb 2013 21:25:00 +0000

While having a discussion about Barry Sharpless with a fellow chemist the following random question occurred to me: How many chemists have contributed at least one significant piece of work to science after winning the Nobel Prize? Sharpless himself invented click chemistry after being recognized for asymmetric synthesis.

After winning the prize many laureates bask in the sunlight and cut down significantly on research. Some use their newfound celebrity status to advance educational or social causes. Others can disappear from the world of science altogether. But a select few plough on as if they had never won the prize and the names of these persistent souls should be more widely known.

A couple of examples spring to mind. At the top of the list should be the man who continued to do research that turned out to be so important that he shared another Nobel Prize for it: Fred Sanger, who got his first Nobel Prize for protein sequencing and the second for DNA sequencing.

R. B. Woodward must also join Fred Sanger at the top. Although technically he won just one Nobel Prize he would have undoubtedly won another (for the Woodward-Hoffmann rules) had he been alive (and cut down on the scotch and cigarettes) and was probably a candidate for a third (ferrocene and organometallic chemistry).

But we can find examples much further back. Ernest Rutherford received an anomalous 1908 prize in chemistry instead of physics, but after winning it he continued to churn out Nobel Prize-winning students and pathbreaking discoveries, including the demonstration of artificial or induced radioactivity. Harold Urey received a prize in 1934 for his discovery of deuterium, but he contributed at least partially to the founding of origins of life chemistry with Stanley Kubrick (ok it's Miller, huge typo, but I am going to let this stay; I can only surmise that I was fantasizing about a Kubrick movie titled "2001 A Space Odyssey: RNA World Edition") in the 50s. In this context Manfred Eigen is another interesting example; after being recognized for methods to study fast reactions in 1967, Eigen embarked on an origins of life career and among other things came up with the idea of "hypercycles".

Interestingly, Linus Pauling who is widely considered the greatest chemist of the twentieth century had exhausted his quota of important chemical discoveries by the time he won the Nobel Prize in 1954. Until then he had already revolutionized the theory of chemical bonding, proposed the alpha helix and beta sheet structures in proteins and had contributed a host of other important ideas ranging from rules for predicting the structure of minerals to proposals about the mechanism of action of antibodies and enzymes. Pauling continued to do interesting work scientific after this, but most of his attention was focused on arms disarmament for which he won the peace prize in 1962. For the rest of his life Pauling was occupied partly with interesting scientific projects and partly with controversial medical projects. Nothing that he did came close to his accomplishments before winning the prize, although given the magnitude of those accomplishments I guess we can cut him some slack.

I don't have an exhaustive list here but I doubt if there's many more names to add here. Doing one piece of significant science in your life seems hard enough so perhaps it's unrealistic to expect two. And yet there are a few hardy souls who achieve this.

Never a simple staple

noreply@blogger.com (Wavefunction) — Tue, 05 Feb 2013 22:12:00 +0000

Stapled peptide. Image: Nature

Carmen Drahl of C&EN has a pretty nice overview of what's happening in the world of stapled peptides. Those who have followed this development are aware of both the promise and the caveats in the area. Interest in constrained peptides was sparked by the observation that helices are involved in a lot of important protein-protein interactions and therapeutics areas. Cancer seems to be an especially prominent target.

The simple thinking is that if you constrain a helix to its helical shape using various chemical strategies, you could minimize the entropic cost of helix formation. In addition, by modulating the properties of whatever chemical group you are using to constrain the structure, you could possibly get better affinity, cell penetration and stability. The strategies used have been varied, from olefin linkers to hydrocarbon linkers, and they have a long history. But stapled peptides have been especially noteworthy; the staple in this case is a short hydrocarbon linker connecting one residue to another a few angstroms away. Based on this idea, groups from Harvard launched a biotech startup named Aileron. Stapled peptides, it seemed were on a promising upward trajectory.

Except that nothing in biology is as simple as it seems. A recent report from groups in Australia and Genentech demonstrated that a previously promising stapled helix which inhibits the antiapoptotic protein Bim is not as potent as it seemed. The problems seem to lie with the fundamental helical structure of the molecule; the paper found that in adding the hydrocarbon staple, you are perturbing some productive intramolecular hydrogen bonding interactions between the residues, and this results in an unfavorable enthalpy of binding.

It's worth reading Carmen's piece not just for the science but for the potential conflict of personalities; science is a human game after all. In this case the conflict arises not only from the Australia/Genentech group's doubts about the original Harvard peptide but the Harvard group's contention that the Australia/Genentech team was in fact looking at the wrong peptide.

Hopefully the misunderstanding will be cleared soon but one thing is clear; this debate seems to be good for science. Constraining helices and other peptides is a completely legitimate way of thinking about improving drug potency and properties, but the devil is in the details. Whenever you put on a constraint you are going to subtly perturb the structure of the molecule, and what seems important here is to investigate how these subtleties will affect the desired functions and properties.

Ultimately stapled peptides are no different from a dozen other drug design strategies. There are cases where they will work and cases where they won't, and any efforts to tease these differences apart will advance the science. Neither stapled peptides nor any other kind of specific drug modification is going to give us the silver bullet. But we already knew this, didn't we?

#Arseniclife reviews: Missing the forest for the trees

noreply@blogger.com (Wavefunction) — Sun, 03 Feb 2013 16:50:00 +0000

In this year's ScienceOnline conference I co-moderated a productive session on peer review in which I pointed out how overly conservative or agenda-driven peer reviews can prevent the publication of legitimate science. Now here's a case where the opposite seems to have occurred; highly questionable science making it through the filter of peer review as easily as particles of dust would make it through a sieve with penny-sized holes.

Thanks to the Freedom of Information Act, USA Today and a couple of other scientists got their hands on the reviews of the infamous #arseniclife paper. There were three reviewers of the study, and all of them approved the paper for publication.

What's interesting is how effortlessly the reviewers miss the forest for the trees. We of course have the benefit of hindsight here, but it's still striking how all three reviews simply swallow the flawed paper's basic and potentially textbook-changing paradigm - the substitution of arsenic for phosphorus - right off the bat. Once they accept this basic premise, all their other objections can simply be seen as nitpicking and window dressing. Only one reviewer asks questions that come close to questioning the absence of phosphorus in the medium, but even he or she quickly veers off course. Another calls the paper a "rare pleasure" to read, seemingly unaware that the pleasure which the paper has provided comes from an extraordinarily ambitious claim that needs to be vetted as closely as possible.

In fact the reviewers ask good questions about vacuoles seen in the bacterium, about better standards for some of the experiments, about better methods to quantify arsenic in its various forms. They even ask a few very chemical questions regarding bond distances. But all these questions are somewhat beside the point since they flow from a fundamentally flawed belief.

When I was in graduate school, the most important thing that my advisor taught me was to always question the assumptions behind a study. If you don't do this, it's easy to be seduced by the technical details of the experiment and to let these details convince you that the basic premise is validated. That's what seems to me to have happened here. All the reviewers seem to have been sucked into legitimate and interesting questions about minutiae. But all the time they forget that what really needs to be questioned is the giant assumption from which all the minutiae have been derived, an assumption that we now know does not stand up to scrutiny. There's an important lesson here.

Andrew Grant

noreply@blogger.com (Wavefunction) — Fri, 25 Jan 2013 21:24:00 +0000

Andrew Grant's name may not be known to everyone, but he was a well-known computational chemist who made some very original contributions to the field. For most of his career he worked at AstraZeneca.

A few days ago he tragically passed away from a massive heart attack while still in excellent health and in his 40s. Makes you appreciate how fortunate you are to be alive and how fragile your time on this planet is. Although I never met him, I remember him giving a talk at OpenEye a few years ago on electrostatics. I remember an unassuming, cheerful man who was clearly passionate about his science.

Grant's longtime friend and colleague Anthony Nicholls of OpenEye has a moving and informative tribute on his webpage. As Anthony notes, wholly original contributions in the field of molecular modeling have been very rare.

"More than just encouragement, he gave ideas. Before he had settled in Macclesfield he had spent a year in the Wilmington branch, working with Brian Masek. Brian had been playing around with the superposition of molecules represented as fused spheres. The code he had written was slow and prone to getting stuck in local minima, but when it worked it gave strikingly good overlays. While Andy was with Harold Scheraga, he had been given the task of seeing how one might use Gaussians to calculate a robust and rapid estimate of molecular area- a problem he had not solved. However, he had worked with Professor Barry Pickup at Sheffield University, his PhD advisor, on the concept of representing molecular volumes with Gaussians. In fact, although it is little appreciated, I think that work with Barry and Maria Gallardo, who became his long-time partner, was one of the best ever in the modeling of molecules. It is highly unintuitive that one can use Gaussians to not just represent the volume of an atom, many had been drawn to that concept before, but to use the convolution formula for Gaussians to represent spherical overlaps- to any order! Pure genius. And the result- that you could model the fused sphere volume to within 0.1%- I do believe is the most remarkable result I have ever seen in our field."

Virtual shock

noreply@blogger.com (Wavefunction) — Thu, 24 Jan 2013 12:54:00 +0000

The Raspberry Pi computer sat innocently in the glove box. This particular glove box was military-grade, enclosed on all sides except one by an inch of reinforced steel, with a narrow porthole made from Pyrex for viewing and manipulation. A robotic arm allowed you to punch the keys. We gratifyingly thought of the $35 units that we had purchased for this project; there’s only so many octa-core Dell Precision Towers that you can blow up every day.

I winced as Alex gingerly started adding yet another nitrogen atom to the ring. It was conventional wisdom, known for ages and duplicated in laboratories around the world. Most explosives including TNT and RDX contained a generous dose of nitrogen atoms; add enough nitrogens to a molecule – preferably a ring – in certain strategic positions and you would almost certainly make a big bang. The bang came from a fundamental property of nitrogen, its tendency to cling to its own kind and eschew others with a fanatical tenacity. It was just basic chemistry, except that it had been put to good use in the service of war and killing for decades.

But nobody had pushed the principle to its limits. Not like this.

The idea came from a recent publication from Prof. Klapötke’s group in Munich. They had synthesized azidoazide azide. That tongue twister gave away the identity of the beast; “azide” was chemical lingo for a group of three nitrogens strung together in a line. Azides are notoriously explosive; lead azide for instance consists of a single lead atom decorated with six nitrogens (two azides), waiting to blow anyone who approaches them to kingdom come. Azidoazide azide sported no less than eight nitrogens tightly knit around a ring. The resulting molecular entity was so unstable that it literally disintegrated the moment it was born. As veteran chemist and blogger Derek Lowe described it,

“The compound exploded in solution, it exploded on any attempts to touch or move the solid, and (most interestingly) it exploded when they were trying to get an infrared spectrum of it. The papers mention several detonations inside the Raman spectrometer as soon as the laser source was turned on”.

Basically the thing exploded no matter what you did or didn’t do to it. The infrared spectrum was a harmless thing, a common experimental technique only supposed to aid in deciphering the structure of a molecule based on the vibrations of bonds between specific atoms. But the mercurial fiend was so remarkably unstable that it was a miracle it could yield itself to being described in a respectable journal, let alone be subjected to the indignities of infrared radiation.

It was after reading the paper that Alex had a brainwave. Azidoazide azide clearly blew up as soon as it was made. What if we designed an explosive that actually blew up before it was made? Preferably the moment it was drawn on a computer and optimized into a realistic structure with normal bond lengths and angles. We could call it a pre-explosive. You could always run the risk that such a compound blew up when it was doodled on a paper napkin by that workaholic chemist even as his kids were playing scrabble in the living room, but everyone knew that decades of graduate school training had done nothing to obliterate chemists’ bad molecular drawings with nonsensical bond lengths and angles. No risk there.

It would be the perfect weapon. Ideally we would want tantalizing features of the molecule – perhaps an infrared spectrum, maybe a melting point, even a few steps of the enabling reaction – to somehow fall into the hands of the enemy. This could be accomplished using a double agent or a spy who willingly allowed herself to be captured with key documents. Once the enemy located the details of the characterization, they would no doubt think that they now possessed the recipe for a key weapon of strategic importance; perhaps a new chemical or debilitating agent, a revolutionary material for armor or a life-saving battlefield drug. All resources would be focused on figuring out the molecular structure of this potential bonanza by working backwards from its properties.

Now all that we would have to do is wait for them to try to reverse-engineer the molecule. Of course, everything’s that’s reverse-engineered these days has to first pass through a computer model. There is no better way to unearth a plausible structural gem from the dross of incomplete data than by using one of those new neural network-enhanced quantum genetic algorithms. The number of possible structures corresponding to such sparse data is astronomical and only a computer can cycle through these endless wannabes. But thanks to D-Wave’s pioneering work, computing power has progressed to such an extent now that commercial software can search roughly ten trillion molecular possibilities in a matter of hours. Once the enemy lets its computing power loose on our data, their computer transforms itself into a literal time bomb even as it cycles through the list of possible structures. Since the algorithm is random, the correct structure may come up within a few seconds or it may be the last one on the list. But what’s certain is that at some point it will appear, and the rest will literally be history. History scattered around in the form of discrete particulate matter.

We waited with bated breath the first time we did it, allowing the molecular structure to relax and optimize its energy. We don’t know exactly what happened as the convergence cycles came to a standstill and the initially deformed bonds started to look normally formed. They found both of us stretched out on the floor. Fortunately this first attempt had only resulted in a design with a modest PEDI (Pre-Explosive Detonation Impact) factor of 5.2, hardly sufficient to cause maiming or death; theory predicts that we would need a PEDI of at least 40 to cause damage equivalent to that caused by the most powerful non-nuclear explosive. But after the mishap the computers were duly installed in a robot-controlled glove box with reinforced walls. The plan was to ramp up the PEDI in a respectable, controlled manner.

It’s a particularly nice day outside as Alex is about to fire up a calculation on a potential molecular candidate. “Remind me what you are doing, again. I have to admit I was too groggy when you excitedly called me in the middle of the night yesterday”. “Well, it was one of those obscure new open-access journals they keep emailing us about. Usually I delete the emails the moment I see them, but this one had something in the title about azides so I took a look. There was a paper from some group in Latvia, from a university I have never heard of. Conforming to the shoddy standards in these journals, there was apparently a lot of characterization but few specific structures except for two general scaffolds, both similar to the work done at Toulouse on low-yield azides in the 80s; I guess Raman spectrometers are cheap and they were obsessed with patent filings. Thought I would reverse-engineer one of them just to see what it looks like.”

The computer displays elegant ball-and-stick structures in front of us as I absent-mindedly listen to Alex and tap my fingers on the side of the glove box. Alex’s quip about open-access journals makes me think of that article in Nature published a few months back which talked about the nuisance created by the proliferation of spurious open-access journals. Many of these use fake fronts, email addresses and entire made-up office locations to convince readers of their authenticity. Most ask you to foot the publishing fees and then disappear. I bet you would find no trace of their whereabouts if you actually decided to look for them. Of course you probably deserved it if you were credulous enough to fall for an unknown publication from a made-up source.

Suddenly something snaps inside me. I get up, startled, and look at Alex, even as he watches the computer flash a structure with a particularly beautiful geometric arrangement of atoms. Oxygens are flaming red, nitrogens are a tranquil blue.

Six thousand miles away in Kiev, a man sits sipping coffee in a café near the old town square. His cell phone rings and a gruff voice communicates the message. The man hangs up and mutters to himself, “45”. His face breaks into a faint, satisfied smile. He goes back to sipping his coffee.

This post was inspired by a spoof article by Isaac Asimov. In the 1940s Asimov was working on a rather thankless Ph.D. at Columbia University. Part of his work involved investigating the properties of compounds which were highly soluble in water. Some of these chemicals were so highly soluble that they seemed to dissolve almost instantly. This behavior encouraged Asimov to pen a spoof article titled “The Endochronic Properties of Resublimated Thiotimoline” about a compound that actually dissolves before it hits the water. Recent articles on new explosives that seem to literally detonate as soon as they are formed lead me to similar thinking…

First published on Scientific American Blogs.

The GPCR Network: A model for open scientific collaboration

noreply@blogger.com (Wavefunction) — Thu, 17 Jan 2013 14:16:00 +0000

This post was first published on the Scientific American Blog Network

: The complexity of GPCRs is illustrated by this mechanical view of their workings (Image: Scripps Research Institute)

G Protein-Coupled Receptors (GPCRs) are the messengers of the human body, key proteins whose ubiquitous importance was validated by the 2012 Nobel Prize in chemistry. As I mentioned in a post written after the announcement of the prize, GPCRs are involved in virtually every physiological process you can think of, from sensing colors, flavors and smells to the action of neurotransmitters and hormones. In addition they are of enormous commercial importance, with something like 30% of marketed drugs binding to these proteins and regulating their function. These drugs include everything from antidepressants to blood-pressure lowering medications.

But GPCRs are also notoriously hard to study. They are hard to isolate from their protective lipid cell membrane, hard to crystallize and hard to coax into giving up their molecular secrets. One reason the Nobel Prize was awarded was because the two researchers – Robert Lefkowitz and Brian Kobilka – perfected techniques to isolate, stabilize, crystallize and study these complex proteins. But there’s still a long way to go. There are almost 800 GPCRs, out of which ‘only’ 16 have been crystallized during the past decade or so. In addition all the studied GPCRs are from the so-called Class A family. There’s still five classes left to decipher, and these contain many important receptors including the ones involved in smell. Clearly it’s going to be a long time before we can get a handle on the majority of these important proteins.

Fortunately there’s something important that GPCR researchers have realized; it’s the fact that many of these GPCRs have amino acid sequences that are similar. If you know what experimental conditions work for one protein, perhaps you can use the same conditions for another similar GPCR. Even for dissimilar proteins one can bootstrap based on existing knowledge. Based on the similarity you could also build computer models for related proteins. Finally, you can use a small organic molecule like a drug to essentially serve as a clamp that helps stabilize and crystallize the GPCR.

But all this knowledge represents a distributed body of work, spread over the labs of researchers worldwide and expected to be sequestered by them for their own benefits. These individual researchers working in isolation would not only face an uphill battle in figuring out the right conditions for studying their proteins but would also run the risk of reinventing the wheel and duplicating conditions from other laboratories. The central question asked by all these researchers is, how does the binding of a small molecule like a drug on the outside of a GPCR lead to the transmission of a signal to the inside?

Enter the GPCR Network, a model of collaborative science which promises to serve as a fine blueprint for other similar efforts. The network was created through a funding opportunity from the National Institute of General Medical Sciences in 2010 and has set itself the goal of structurally characterizing 15-25 GPCRs in the next five years. The effort is based at the Scripps Research Institute in La Holla and involves at least a dozen academic and industrial labs.

So how does this network work? The idea for the network came from the recognition that there are hundreds of GPCR researchers spread across the world. Each one is an expert on a particular GPCR but each one has largely worked separately. What the network does is to leverage the expertise from one researcher’s lab and apply it a similar GPCR in another lab (there are technical criteria for defining ‘similarity’ in this case). There are a variety of very useful protocols, ideas and equipment that can be shared between labs. This sharing cuts down on redundant protocols, saves money and accelerates the resolution of new GPCR puzzles much faster than what could be achieved individually.

For instance, a favorite strategy for stabilizing a GPCR involves tagging it with an antibody that essentially holds the protein together. An antibody that worked for one GPCR can be lent to a researcher who is investigating another GPCR with a similar amino acid sequence. Or perhaps there is a chemist who has discovered a new molecule that binds very tightly to a particular receptor. The network would put him in touch with a crystallographer who could use that molecule to fish out that GPCR from a soup of other proteins and crystallize it. Once the crystallographer solves the structure of the protein using this molecule, he or she could then send the structure to a computer modeler who can use it to build a structure for another particularly stubborn GPCR which could not be crystallized. The computer model might explain some unexpected observations from a fellow network researcher who was using a novel instrumental technique. This novel technique would then be shared with everyone else for further studies.

Thus, what has happened here is that the individual pockets of knowledge from a biochemist, organic chemist, crystallographer and computer modeler – none of whom would have proceeded very far by themselves – are merged together to provide an integrated picture of a few important GPCRs. The entire pipeline of protocols including protein isolation, purification, structure determination and modeling also serves as a feedback loop, with insights from one step constantly informing and enriching others. This represents a fine example of how collaborative and open research can accelerate important research and save time and money. It's to the credit of these scientists that they haven't held their valuable reagents and techniques close to their chest but are sharing them for everyone's benefit.

In the three years since it has been up and running, the GPCR Network has leveraged the expertise of many experts in generating insights into the structure and function of important receptors. Its collaborative efforts have resulted in eight protein structures in just two years. These include the adenosine receptor which mediates the effect of caffeine, the opioid receptor which is the target for morphine and the dopamine receptor which binds to dopamine. Every one of these collaborations involved a dozen or so researchers across at least three or four labs, with each lab employing its particular area of expertise. Gratifyingly, there’s also a few industrial labs involved in the efforts and we can hope that this number will increase even as the pharmaceutical industry becomes more collaborative.

It’s also worth noting that the network was funded by the NIGMS, an institution which has been subject to the whims of budget and personnel cuts. This institution is now responsible for an effort that’s not only accelerating research in a fundamental biological area but is also contributing to a better understanding of existing and future drugs. Scientists, politicians and members of the public who are seeking a validation of basic, curiosity-driven scientific research and reasons to fund it shouldn’t have to look for.

Review on N-methylation

noreply@blogger.com (Wavefunction) — Fri, 11 Jan 2013 18:51:00 +0000

Veteran peptide chemist Horst Kessler (TU Munich) has a good review on the effects of N-methylation of peptides and proteins in a recent issue of Angewandte Chemie. N-methylation has been an interesting and frequently productive strategy for a long time, but the main problem was that the chemistry needed to implement it wasn't there yet. But thanks to new developments chemists have caught up and selective N-methylation of amides no longer needs to be the rate-limiting step that it was.

N-methylation has a variety of interesting and potentially very useful effects on small molecule and peptide conformation and function. For one thing, N-methylated amide bonds have a different distribution of cis and trans forms which is somewhat more evenly distributed than that in non N-methylated amide bonds which dominantly prefer the trans conformation. This can significantly tweak the distribution of conformations in solution.

From a biological standpoint things get even more interesting. N-methylation makes the molecule more lipophilic and therefore more membrane-permeable, improving cell penetration. It gets rid of one hydrogen bonding N-H bond. This can sometimes have an unfavorable effect on permeability if that N-H forms an intramolecular hydrogen bond, but often it can help. Intramolecular hydrogen bonds are another valuable tactic for hiding polar surface area and improving permeability. The ideal situation is a combination of both N-methylation and intramolecular hydrogen bonding, exemplified by the archetypal "large", complex, biologically active drug, cyclosporine. Recent studies by the Jacobson (UCSF) and Lokey (groups) have described strategies for both specific N-methylation chemistry and for predicting permeability using computational calculations.

Finally, N-methylation can prevent recognition and cleavage by peptidases which recognize "normal" amide bonds, especially when the N-methylated amides are part of a cyclic peptide. All these factors can significantly improve bioavailability. Kessler talks about all of them and illustrates these principles with a few striking examples, including somatostatin, amanitin and melanocortin. Many of these sport similar motifs, leading to ideas for possible design of standardized building blocks for improving permeability and bioavailability. The piece is worth a look if you are into developing peptides and peptidomimetics as drugs or even more generally if you are interested in peptide and small molecule conformations.

The value of long-term vision

noreply@blogger.com (Wavefunction) — Thu, 10 Jan 2013 14:54:00 +0000

Friend and fellow blogger David Kroll has a great profile of Bob Lefkowitz, last year's chemistry Nobel Laureate from Duke. The most striking thing for me was to read about how Duke bent over backwards and went to unbelievable lengths to get Lefkowitz on their faculty in the 70s. Says something about the value of long-term vision and investment in basic research, something that sadly seems to be exceedingly lacking these days.

"Lefkowitz almost didn't make it to Duke. He had already committed to practicing medicine at the Massachusetts General Hospital of Harvard University after his service commitment. After six months there, "I really missed the lab," Lefkowitz recalls, adding he was "like a junkie who needed a fix."

Meanwhile, 600 miles south in Durham, the medical school at Duke University was flourishing. Dr. Andy Wallace, chief of cardiology, had seen the young Lefkowitz present his receptor studies at an American Heart Association meeting. He and Dr. Jim Wyngaarden, chairman of medicine, they tried to lure Lefkowitz to Duke. However, Harvard had already promised Lefkowitz a faculty position after his cardiology fellowship.

Lefkowitz admits he had no intention of coming to Duke and politely rejected Duke's offer. But Wallace and Wyngaarden rejected Lefkowitz's rejection. Their counteroffer included a $32,000 annual salary—the equivalent of $165,000 today (the initial offer was $24,000)—and an open-ended request for his other needs.

Still thinking Duke wasn't in his future, he responded with "outrageous demands" Lefkowitz says. One of those was that he start as an associate professor with academic tenure, a position that requires rigorous review at seven to 11 years of faculty service. He was just 30, straight out of his fellowship.

"That was the most outrageous demand and that was the one put in there to scotch the whole deal because I didn't want to come," Lefkowitz says. "The whole purpose of my request was to give me a graceful way out because I knew in my head that what I was asking was impossible."

Wyngaarden and Wallace met every demand.

Lefkowitz was dumbfounded. "Duke was a young institution [in 1973]. But it was a decent institution, and the offer was just so non-comparable with what Harvard was offering that I said, 'This is it. I gotta go for it.'"

"But a lot of people said, 'How can you go to Duke?' Even my in-laws at the time." He reproduces the Yiddish accent: "'Whaddaya, crazy? You're at Hawvaad.' But something said, 'Go for this.'"

Who knew VCs had a sense of humor

noreply@blogger.com (Wavefunction) — Tue, 08 Jan 2013 19:51:00 +0000

So it's the annual J P Morgan Healthcare Conference in California and I see, of all things...#jpmpickuplines on Twitter. I don't know how much these can mitigate the still-dour VC landscape, but hey, at least nobody can blame them for trying to present evidence that they are human.

Chemistry and Biology: Kuhnian or Galisonian?

noreply@blogger.com (Wavefunction) — Mon, 31 Dec 2012 16:48:00 +0000

: Peter Galison who has emphasized the dominance of experimental techniques in engineering scientific revolutions (Image: BNL).

First published on the Scientific American Blog Network.

Freeman Dyson has a perspective in this week's Science magazine in which he provides a summary of a theme he has explored in his book "The Sun, the Genome and the Internet". Dyson's central thesis is that scientific revolutions are driven as much or even more by tools than by ideas. This view runs somewhat contrary to the generally accepted belief regarding the dominance of Kuhnian revolutions - described famously by Thomas Kuhn in his seminal book "The Structure of Scientific Revolutions" - which are engineered by ideas and shifting paradigms. In contrast, in reference to Harvard university historian of science Peter Galison and his book "Image and Logic", Dyson emphasizes the importance of Galisonian revolutions which are driven mainly by experimental tools.

As a chemist I find myself in almost complete agreement with the idea of tool-driven Galisonian revolutions. Chemistry as a discipline rose from the ashes of alchemy, a thoroughly experimental activity. Since then there have been four revolutions in chemistry that can be called Kuhnian. One was the attempt by Lavoisier, Priestley and others at the turn of the 17th century to systematize elements, compounds and mixtures to separate chemistry from the shackles of alchemical mystique. The second was the synthesis of urea by Friedrich Wohler in 1828; this was a paradigm shift in the true sense of the term since it placed substances from living organisms into the same realm as those from non-living organisms. The third revolution was the conception of the periodic table by Mendeleev, although this was more of a classification akin to the classification of elementary particles by Murray Gell-Mann and others during the 1960s. A minor revolution accompanying Mendeleev's invention that was paramount for organic chemistry was the development of the structural theory by von Leibig, Kekule and others which led the way to structure determination of molecules. The fourth revolution was the application of quantum mechanics to chemistry and the elucidation of the chemical bond by Pauling, Slater, Mulliken and others. All these advances blazed new trails, but none were as instrumental or overarching as the corresponding revolutions in physics by Newton (mechanics), Carnot, Clausius and others (thermodynamics), Maxwell and Faraday (electromagnetism), Einstein (relativity) and Einstein, Planck and others (quantum mechanics).

Why does chemistry seem more Galisonian and physics seem more Kuhnian? One point that Dyson does not allude to but which I think is cogent concerns the complexity of the science. Physics can be very hard, but chemistry is more complex in that it deals with multilayered, emergent systems that cannot yield themselves to reductionist, first principles approaches. This kind of complexity is also apparent in the branches of physics typically subsumed under the title of "many-body interactions". Many-body interactions range from the behavior of particles in a superconductor to the behavior of stars condensing into galaxies under the influence of their mutual gravitational interaction. There are of course highly developed theoretical frameworks to describe both kinds of interactions, but they involve several approximations and simplifications, resulting in models rather than theories. My contention is that the explanation of more complex systems, being less amenable to theorizing, are driven by Galisonian revolutions rather than Kuhnian.

Chemistry is a good case in point. Linus Pauling's chemical theory arose from the quantum mechanical treatment of molecules, and more specifically the theory of the simplest molecule, the hydrogen molecular ion which consists of one electron interacting with two nuclei. The parent atom, hydrogen, is the starting point for the discipline of quantum chemistry. Open any quantum chemistry textbook and what follows from this simple system is a series of approximations that allow one to apply quantum mechanics to complex molecules. Today quantum chemistry and more generally theoretical chemistry are highly refined techniques that allow one to explain and often predict the behavior of molecules with hundreds of atoms.

And yet if you look at the insights gained into molecular structure and bonding over the past century, they have come from a handful of key experimental approaches. Foremost among these are x-ray diffraction, which Dyson also mentions, and Nuclear Magnetic Resonance (NMR) spectroscopy, also the basis of MRI. It is hard to overstate the impact that these techniques have had on the determination of the structure of literally millions of molecules ranging across an astonishing range of diversity, from table salt to the ribosome. X-ray diffraction and NMR have provided us not only with the locations of the atoms in a molecule, but also with invaluable insights into the bonding and energetic features of the arrangements. Along with other key spectroscopic methods like infrared spectroscopy, neutron diffraction and fluorescence spectroscopy, x-rays and magnetic resonance have not just revolutionized the practice of chemical science but have also led to the most complete understanding we have yet of chemical bonding. Contrast this wealth of data with similar attempts using purely theoretical techniques which can also be used in principle to predict the structures, properties and functions of molecules. Progress in this area has been remarkable and promising, but it's still orders of magnitude harder to predict, say, the most stable configuration of a simple molecule in a crystal than to actually crystallize the chemical even by trial and error. From materials for solar cells to those for organ transplants, experimental structure determination in chemistry has fast outpaced theoretical prediction.

What about biology? The Galisonian approach in the form of x-ray diffraction and NMR has been spectacularly successful in the application of chemistry to biological systems that culminated in the advent of molecular biology in the twentieth century. Starting with Watson and Crick's solution of the structure of DNA, x-ray diffraction basically helped formulate the theory of nucleic acid and protein structure. Particularly noteworthy is the Sanger method of gene sequencing - an essentially chemical technique - which has had a profound and truly revolutionary impact on genetics and medicine that we are only beginning to appreciate. Yet we are still far from a theory of protein structure in the form of protein folding; that Kuhnian revolution is yet to come. The dominance of Galisonian approaches to biochemistry raise the question about the validity of Kuhnian thinking in the biological sciences. This is an especially relevant question because the last Kuhnian revolution in biology - a synthesis of known facts leading to a general explanatory theory that could encapsulate all of biology - was engineered by Charles Darwin more than 150 years ago. Since then nothing comparable has happened in biological science; as indicated earlier, the theoretical understanding of the genetic code and the central dogma came from experiment rather than the very general synthesis in terms of replicators, variation and fitness that Darwin put together for living organisms. Interestingly, in his later years (and only a year before the discovery of the structure of DNA) the great mathematician John von Neumann put forward a Darwin-like, general theoretical framework that explained how replication and metabolism could be coupled to each other, but this was largely neglected and certainly did not come to the attention of practicing chemists and biologists.

Dyson's essay and the history of science does not necessarily assert that the view of science in terms of Kuhnian revolutions is misguided and that in terms of Galisonian revolutions is justified. It's rather that complex systems are often more prone to Galisonian advances because the theoretical explanations are simply too complicated. Another viewpoint driven home by Dyson is that Kuhnian and Galisonian approaches alternate and build on each other. It is very likely that after a few Galisonian spells a field becomes ripe for a Kuhnian consolidation.

Biology is going to be especially interesting in this regard.

The most exciting areas in current biology are considered to be neuroscience, systems biology and genomics. These fields have been built up from an enormous number of experimentally determined facts but they are in search of general theories. However, it is very likely that a general theoretical understanding of the cell or the brain will come from very different approaches from the reductionist approaches that were so astonishingly successful in the last two hundred years. A Kuhnian revolution to understand biology could likely borrow from its most illustrious practitioner - Charles Darwin. One of the signature features of Darwin's theory is that it seeks to provide a unified understanding that transcends multiple levels of biological organization, from individual to society. Our twenty-first view of biology adds two pieces, genes and culture, to opposite ends of the ladder. It is time to integrate these pieces - obtained by hard, creative Galisonian science - into the Kuhnian edifice of biology.

Nobel Week Dialogue

noreply@blogger.com (Wavefunction) — Mon, 10 Dec 2012 14:46:00 +0000

There hasn't been much blogging over the last two weeks, mainly because I have been blogging for a special event preceding the official Nobel Prize ceremony in Stockholm.

"Nobel Week Dialogue" was a day-long symposium organized by the Nobel committee and other sponsors on December 9. The topic was "The Genomic Revolution and its Impact on Society" and it featured many science and policy leaders including Eric Lander, Steven Chu, James Watson and Craig Mello.

I was invited to write for this event and I have four posts, mainly historical and philosophical, contemplating aspects of the genomic revolution.

1. Physicists in Biology; And Other Quirks of the Genomic Age.

2. An interview with Watson and Crick by Horace Freeland Judson.

3. How they did it.

4. The Third Age of Molecular Biology.