Thanksgiving

When the Protein Data Bank releases a much-awaited protein structure which shows you *exactly* what you wanted to see, it's much like looking at a newly written Mozart symphony. There is a purpose to every single atom and water molecule, a rhythm to every single bond and interaction, a graceful yet deliberate elegance to every single curve of a loop, to every turn of an alpha helix, to the meandering pleats of every beta sheet.

The structure contains precisely the right number of interacting parts, not a single one more or less. Only this time the composer is nature, and the conductor is evolution. Looking at the structure you cannot help but get the feeling that nature has lifted a corner of her great veil for you to gaze in awe and appreciation at the edifice.

I don't say it enough, but today I feel grateful and humbled to be a scientist, to be granted the privilege of being able to sit in my modest little corner of the universe and revel in a movement from this grand performance.

Good luck to B.R.S.M!

B.R.S.M. is off to the US for a postdoc. And he does Woodward Wednesdays. What's not to like.

1. What is your message for BRSM?
It's the only time in your life when (unless you have a family) your only responsibility will be research; no teaching, no exams. Make the most of it while it lasts.

2. What is one postdoc survival tip you would give to BRSM?
Time is of the essence. While it's essential to have fun during your postdoc, you should hit the ground running and start making plans for job applications, grant proposals etc. right away.

3. Do you have a fun story you could share from your postdoc and/or US academic experience?
There was the time when a naive rotation student referred to the abbreviated name of a dye in her powerpoint presentation. Some of us wanted to know the structure, but before we had second thoughts and could stop her, she had already done a Google image search. Turns out the abbreviated dye name was also the name of a porn star. I thought she was going to faint with embarrassment (the rotation student, that is; porn stars never faint with embarrassment).

4. A survival tip for living in the US?
Unless you are living in a city, get a car. You don't want to add to your hectic postdoc schedule by walking in the heat/cold or waiting for the bus that never shows up.

5. What would you like to see on BRSM blog in the future?
More Woodward Wednesdays, naturally.

6. Anything else?

Live long and reflux!

Chemistry, fluid dynamics and an awful radioactive mess

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

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

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

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.