The Curious Wavefunction: September 2013

Phil Baran keeps the dream of classical organic chemists alive

I am very happy to note that organic chemist Phil Baran from Scripps is one of this year's recipients of the MacArthur "Genius" Award. It's rare for a chemist and especially a "pure" organic chemist to receive this recognition.

The first reason why chemists should be happy of course is that Baran is a phenomenal chemist. Ever since he was a graduate student he has been churning out innovative molecules and methods to make them. It's probably safe to say that he is the most promising young organic chemist in the world right now.

But the more important reason why this recognition is almost heart-warming is because it reaffirms faith in the soul of "pure" organic chemistry and synthesis. Baran's style of synthesis reminds one of the golden age of the discipline in the 50s and 60s, when legendary practitioners like Woodward, Corey and Stork used to make molecules for the sake of making them, for exploring the beauty and difficulty of their architectures and for appreciating the simple tricks and reagents that could turn a complex synthesis into a simple one. Phil Baran produces the same wistful nostalgia in a young aspiring organic chemist that a Detroit car manufacturer from the 50s would produce in a young automobile engineer standing on the empty grounds of a once-thriving factory. He reminds us of the time when synthesis was king.

Throughout his career Baran has continued to achieve all the goals savored by the giants of synthesis. He has followed his mentor E J Corey in synthesizing some very complex compounds as well as in developing new methods. When I read about his work I think of the young Woodward making reserpine or of the young Corey discovering new protecting groups for alcohols.

The last few years have seen some cynicism - much of it well-directed - about total synthesis, about the tendency to treat molecule-making as a marathon rather than a sprint. And yet young Baran has proven that there are still gems to be unearthed from the dross of hammer and tong chemistry, and that there is still hope for the next generation of purely synthetic chemists who are looking for truly innovative molecules and methods.

This seems to me to be a more than adequate reason to toast Baran and his accomplishments. Congratulations Phil!

2013 Nobel Prizes

It's almost time for the 2013 Nobel Prizes, which means it's also time for playing that little game which we in the chemosphere have been playing for a while. As a prize predictor my record hasn't been execrable; in the last few years I did get most of the prizewinners for the ribosome, palladium-catalyzed chemistry, GFP and GPCRs right. Out of these the ones that really count are the ribosome and GPCRs, since I actually predicted the winners during the year in which they won.

As I mentioned in last year's list, predictions for the prize get somewhat easier every year when all you have to do is to keep old predictions and get rid of recent hits. Having perpetual favorites definitely makes the job easier. What does change is the probability of prediction based on last year's prizes. So without further ado, here is a modified and updated list from last year with a modified set of probabilities.

Let's start by noting that since last year's prize was awarded to biochemists, it makes it less likely that the same field will be recognized this year. Excluding biochemistry, the fields that top my list for this year are instrumental techniques and energy. Physical chemistry has also not won since Gerhard Ertl received the prize for surface chemistry. NMR and single-molecule spectroscopy both seem to me to be fields whose time is due. As for energy, I don't see anyone in solar or wind who has made enough headway to warrant a prize. However the inventors of lithium ion batteries definitely seem to deserve one.

As usual the predictions are classified as "easy" or "difficult" depending on their likelihood of winning. Note also that Nobel Prizes have traditionally been handed out to specific discoveries rather than for lifetime achievements, although the latter have not been entirely missing from the list.

Single-molecule spectroscopy (Easy)
Pros: The field has obviously matured and is now a powerful tool for exploring everything from nanoparticles to DNA. It’s been touted as a candidate for years. The frontrunners seem to be W E Moerner and M Orrit, although Richard Zare has also been floated often.
Cons: The only con I can think of is that the field might yet be too new for a prize.

NMR (Difficult): It’s been a while since Kurt Wuthrich won the prize for NMR. But it’s been even longer since a prize was awarded for methodological developments in the field (Richard Ernst). I don’t know enough about the field to know who the top contenders would be, but Ad Bax and Alexander Pines seem to have really made pioneering contributions. Pines especially helped launch the field of solid-state NMR which as a field certainly seems to deserve a Nobel at some point.

While we are on the topic of instrumental techniques, it's also worthwhile to mull over some methods that have become household words in both academia and industry. These methods may not be as earth-shattering as NMR but these days they are certainly as commonplace as NMR. What about surface plasmon resonance which is routinely used to measure binding of all kinds of molecules to each other? Wikipedia tells me that "The first SPR immunoassay was proposed in 1983 by Liedberg, Nylander, and Lundström, then of the Linköping Institute of Technology (Sweden)", so I don't know if these gentlemen should be up for the prize (the three form a neat, Nobel-approved trio). FRET also comes to mind. Then there's cryoelectron microscopy which while tantalizing is almost certainly too nascent a field to be recognized.

Moving on to energy, there's one development that undoubtedly tugs at my heartstrings:

Lithium-ion batteries (Moderately easy): Used in almost every kind of consumer electronics, lithium-ion batteries are also touted as the best battery alternative to fossil fuels. A great account is provided in Seth Fletcher’s “Bottled Lightning”. From what I have read in that book and other sources, John Goodenough, Stanley Whittingham and Akira Yoshino seem to be the top candidates, although others have also made important contributions and it may be hard to divide up the credit.

And two other fields, at least one of which has been a favorite for a while:

Electron transfer in biological systems (Easy)
Pros: Another field which has matured and has been well-validated. Gray and Bard seem to be leading candidates.

Computational chemistry and biochemistry (Difficult):

Pros: Computational chemistry as a field has not been recognized since 1998 so the time seems due. One obvious candidate would be Martin Karplus. Another would be Norman Allinger, the pioneer of molecular mechanics.

Cons: This would definitely be a "lifetime achievement award". Karplus did do the first MD simulation of a protein ever but that by itself wouldn’t command a Nobel Prize.

The other question is regarding what field exactly the prize would honor. If it’s specifically applications to biochemistry, then Karplus alone would probably suffice. But if the prize is for computational methods and applications in general, then others would also have to be considered, most notably Allinger but perhaps also Ken Houk who has been foremost in applying such methods to organic chemistry. Another interesting candidate is David Baker whose program Rosetta has really produced some fantastic results in predicting protein structure and folding. It even spawned a cool game. But the field is probably too new for a prize and would have to be further validated; at some point I do see a prize for biomolecular simulation.

If they really do decide to give out another award for biochemistry, there are some well-recognized candidates. Many of these are also shoe-ins for the medicine prize.

Nuclear receptors (Easy): Pros: The importance of these proteins is unquestioned. I worked a little on NRs during my postdoc and remember being awed by the sheer diversity and ubiquity of these molecules in mediating key physiological functions. In addition they are already robust drug targets, with drugs like tamoxifen that hit the estrogen receptor making hundreds of millions of dollars. Most predictors seem to converge on the names of Chambon and Evans this prediction and NRs are definitely at the top of my list.

Chaperones: (Easy): Arthur Horwich and Franz-Ulrich Hartl just won last year’s Lasker Award for their discovery of chaperones. Their names have been high on the list for some time now.
Pros: Clearly important. Chaperones are not only important for studying protein folding on a basic level but in the last few years the malfunctioning of chaperones such as heat-shock proteins has been shown to be very relevant to diseases like cancer.

Cons: Too early? Probably not.

Statins (Difficult): Akira Endo’s name does not seem to have been discussed much. Endo discovered the first statin. Although this particular compound was not a blockbuster drug, since then statins have revolutionized the treatment of heart disease.

Pros: The “importance” as described in Nobel’s will is obvious since statins have become the best-selling drugs in history. It also might be a nice statement to award the prize to the discovery of a drug for a change. Who knows, it might even boost the image of a much maligned pharmaceutical industry...
Cons: The committee is not really known for awarding actual drug discovery. Precedents like Alexander Fleming (antibiotics), James Black (beta blockers, antiulcer drugs) and Gertrude Elion (immunosuppresants, anticancer agents) exist but are far and few in between. On the other hand this fact might make a prize for drug discovery overdue.

Drug delivery (Difficult): A lot of people are pointing to Robert Langer for his undoubtedly prolific and key contributions to drug delivery. The field as a whole has not been recognized yet so the time may be ripe; from my own understanding of his contributions, Langer seems to me more of an all-rounder, although it may not be too late to single out some of his earlier discoveries, such as the first demonstration of the delivery of high molecular weight polymer drugs.

Cancer genetics (Easy): Clearly a very important and cutting-edge field. We still don’t know how much of an impact genomic approaches will ultimately have on cancer therapy since the paradigm is clearly evolving and traps abound, but any history of the field will have to include Robert Weinberg and Bert Vogelstein. Vogelstein discovered the importance of p53, the “guardian of the genome” while Weinberg discovered the first oncogenes. In addition both men have also been prominent influences on the field as a whole. Given both the pure and applied importance of their work, their discoveries should fit the Nobel committee’s preferences like a glove. As a con, the field is very vast and divvying up credit could be tricky.

Genomics (Difficult): A lot of people say that Venter should get the prize, but it’s not clear exactly for what. Not for the human genome, which others would deserve too. If a prize was to be given out for synthetic biology, it’s almost certainly premature. Venter’s synthetic organisms from last year may rule the world, but for now we humans still prevail. On the other hand, a possible prize for genomics may rope in people like Carruthers and Hood who pioneered methods for DNA synthesis.

DNA fingerprinting (Easy): Now this seems to me to be very much a field from the “obvious” category and one that's long overdue. The impact of DNA fingerprinting and Western and Southern Blots on pure and applied science- everything from discovering new drugs to hunting down serial killers (and exonerating wrongly convicted ones; for instance check out this great article by Carmen Drahl in C&EN)- is at least as big as the prizeworthy PCR. I think the committee would be doing itself a favor by honoring Jeffreys, Stark, Burnette and Southern. And while we are on DNA, I think it’s also worth throwing in Marvin Caruthers whose technique for DNA synthesis really transformed the field. In fact it would be nice to award a dual kind of prize for DNA- for both synthesis and diagnosis.Cons: Picking three might be tricky.

Chemical genetics (Easy): Another favorite for years, with Stuart Schreiber and Peter Schultz being touted as leading candidates. Pros: The general field has had a significant impact on basic and applied scienceCons: This again would be more of a lifetime achievement award which is rare. Plus, there are several individuals in recent years (Cravatt, Bertozzi, Shokat) who have contributed to the field. It may make some sense to award Schreiber a ‘pioneer’ award for raising ‘awareness’ but that’s sure going to make at least some people unhappy. Also, a prize for chemical biology might be yet another one whose time has just passed, just like a prize for the Pill.

Speaking of the pill, Carl Djerassi's 90th birthday was celebrated this year at the ACS National Meeting in Indianapolis. For the past thirty odd years Djerassi has been focused not on science but on poetry and writing. Personally I think that recognizing him with the prize would still be a nice thing - after all, the social impact of the easily equals that of other prizewinning discoveries like IVF - but the late receipt of the prize combined with the death of many important associates would make it all a bit strange.

What about the physics prize?

As interesting as the chemistry prize is going to be, its significance and excitement might pale to a whimpering whisper in comparison to the physics Nobel Prize, the awarding of which might create a controversy the likes of which have not been seen since Miley Cyrus took to the stage with a novel dance form.

The problem is simple. Everybody agrees that the discovery of the Higgs boson deserves a Nobel Prize. But almost every history of the Higgs credits at least six and possibly seven people with laying out the ideas that predicted the finding. Again, nobody denies that Peter Higgs deserves the prize, but after that it's anybody's guess. And the six people often cited are just the theoreticians; including the experimenters at CERN adds another well-deserved layer of complexity to giving out the prize.

If we are really looking for least-of-all-evil type scenarios then perhaps they can award the prize to Higgs and collectively to the CERN team. That way fewer feathers may be ruffled (or at least all feathers would be equally ruffled) and the prize would also have been squarely divided among the lead theoretician and the experimenters. We will see. This year's Nobel Prize for Physics may put some of the great Greek dramas to shame.

Update: As David Pendlebury from Thomson Reuters correctly pointed out to me, Vogelstein did not discover p53 but was the first to point out its connection to cancer as a common denominator. Also, Elwood Jensen passed away last year.

Update: Other predictions - Pipeline, Chembark, Chemistry World.

MIT and chemistry: What gives?

A reference to pioneering physical organic chemist Jack Roberts in a C&EN article again brought the following question to my mind: Why has MIT, over several decades, managed to lose some of the best chemists in the world to other departments? This question has been nagging at me for several years and resurfaced recently when Dan Nocera moved to Harvard from MIT.

I understand that my information is largely anecdotal, but it seems to me that the school has lost more highly accomplished chemists to other departments than pretty much any other top school.

Of course, since these chemists were attracted to MIT in the first place that says something about the caliber of the department, but why lose them then?

Here's a tentative list of MIT chemists who have been successfully lured away. What is striking about the list is that it spans at least four decades and includes some of the most distinguished scientists of those four decades. Also interesting to note that most of these are organic/bioorganic guys so that could say something about what areas the department is focused on.

Jack Roberts (Caltech)
George Whitesides (Harvard)
Chris Walsh (Harvard)
Barry Sharpless (Scripps)
Peter Seeberger (Max Planck)
Greg Fu (Caltech)
Dan Nocera (Harvard)

Who else am I leaving out? I don't want to speculate on the reasons; a simple one could be that not every school focuses equally on all its disciplines. And nobody can deny that MIT chemistry has still been top notch over the decades; as I indicated before, the very fact that all these people launched their careers there vouches for the quality of the department. But the track record seems to indicate that MIT is much better at attracting people than retaining them. And there's got to be a reason for that.

Chemical and Engineering News celebrates 90 years: How chemistry has come a long way

: Chemistry is - in the true sense - the central science, reaching inside every aspect of our lives (Image: Marquette University)

Chemical and Engineering News (C&EN) is celebrating 90 years of its existence this year, and I can only imagine how perplexed and awestruck its editors from 1923 would have been had they witnessed the state of pure and applied chemistry in 2013. I still remember devouring the articles published in the magazine during its 75th anniversary, and this anniversary also offers some tasty perspectives on a diverse smattering of topics; catalysis, structural biology and computational chemistry to name a few.

There's an article in the magazine documenting how the single-most important concept in chemistry - that of the chemical bond - has undergone a transformation; from fuzzy, to rigorously defined, to fuzzy again (although in a very different sense).

Nobel Laureate Roald Hoffmann had something characteristically insightful to say about The Bond:

"My advice is this: Push the concept to its limits. Be aware of the different experimental and theoretical measures out there. Accept that at the limits a bond will be a bond by some criteria, maybe not others. Respect chemical tradition, relax, and instead of wringing your hands about how terrible it is that this concept cannot be unambiguously defined, have fun with the fuzzy richness of the idea.”

In a bigger sense the change in chemistry during these 90 years has been no less than astounding. In 1923 the chemical industry already made up the foundations of a great deal of daily life, but there was little understanding of how to use the concepts and products of chemical science in a rational manner. Since 1923 our knowledge of both the most important aspect of pure chemistry (the chemical bond) and of applied chemistry (synthesis) has grown beyond the wildest dreams of chemistry's founders.

If we had to pinpoint two developments in chemistry during these 90 years that would truly be described as "paradigm shifts", they would be the theoretical understanding of bonding and the revolution in instrumental analysis. As I and others have argued before, chemistry unlike physics is more "Galisonian" than "Kuhnian", relying as much on new instrumental techniques as on conceptual leaps for its signal achievements.

The two most important experimental advances in chemistry - x-ray diffraction and nuclear magnetic resonance - both came from physics, but it was chemists who honed these concepts into a routine laboratory tool for the structure determination of a staggeringly diverse array of substances, from table salt to theribosome. The impact of these two developments on chemistry, biology, medicine and materials science cannot be underestimated; they cut down the painstaking task of molecular structure determination from months to hours, they allowed us to find out the nature of novel drugs, plastics and textiles and they are now used by every graduate student every single day to probe the structure of matter and synthesize new forms of it. Other developments like infrared spectroscopy, electron diffraction, atomic force microscopy and single molecule spectroscopy are taking chemistry in novel directions.

The most important theoretical development in chemistry also derived from physics, but its progress against demonstrates chemists' central role in acting as mediators between concept and application. It also serves to make a key point about reductionism and the drawbacks of trying to reduce chemistry to physics. The chemical bond is an abstract concept going back to "affinities" between atoms (which when illustrated were replete with hooks and eyes). But it was in 1923 that the great American chemist G. N. Lewis propounded the idea in terms of atoms sharing electrons. This was a revolutionary brainwave and illuminated the way for Linus Pauling, John Slater, Robert Mulliken, John Pople and others to use the newly developed machinery of quantum mechanics to fashion the qualitative principle into an accurate, quantitative tool which - with the development of modern computing - now allows chemists to routinely calculate and predict important properties for any number of chemical substances.

Yet the ramifications of the chemical bond tempt and beguile physicists and constantly escape from their grasp when they try to define them too accurately. The above quote by Roald Hoffmann puts the problem in perspective; quintessentially chemical ideas like aromaticity, the hydrophobic effect, steric effects and polarity "fray at the edges" (in Hoffmann's words) when you try to push them to their limits and try to define them in terms of subatomic physics. Chemistry is a great example of an emergent discipline. It is derived from physics and yet independent of it, relying on fundamental definitions at its own level when progressing.

The chemical bond and other theoretical aspects of chemistry have enabled the rise of the one activity pursued by chemists of which society is an unsurpassed beneficiary - the science, art and commerce of synthesis. Every single molecule that bathes, clothes, feeds, warms, transports and heals us has been either derived from nature using chemical techniques or has been synthetically made in a chemical laboratory. The social impact of these substances is hard to underestimate; even a sampling of a few such as the contraceptive pill, antibiotics or nylon attests to the awesome power of chemistry to completely transform our lives.

In 1923 synthesis was a haphazard process and there was virtually no understanding of how we could do it rationally. All of this changed in the 1950s and 60s when a group of pioneering scientists led by the legendary organic chemist Robert Burns Woodward revolutionized the process and honed synthesis into a precisely rational science which took advantage of the course of chemical reactions, the alignment of orbitals, the development of new chemical reagents and the three-dimensional shape of molecules. Many Nobel Prizes were handed out for these groundbreaking discoveries, but none surpassed the sheer impact that synthesis will continue to have on our way of life.

As is inevitably the case for our embrace of science and technology, with progress also come problems, and chemists have had to deal with their share of issues like environmental pollution, drug side effects and the public perception of chemistry. Suffice it to say that most chemists are well aware of these and are working hard to address them. They recognize that with knowledge comes responsibility, and the responsibility they bear to mitigate the ills of the wrongful application of their science transcends their narrow professional interests and encompasses their duties as citizens.

In the new century chemistry continues to build upon its past and chemists continue to push its boundaries. Another change which the editors of C&EN would not have foreseen in 1923 is the complete integration of chemistry into other disciplines like biology, medicine and engineering and its coming into its own as the true "central science". Today chemistry deeply reaches into every single aspect of our lives. The cardinal problems facing civilization - clean and abundant food and water, healthcare, national security, overpopulation, poverty, climate change and energy - cannot be solved without a knowledge of chemistry. Simply put, a world without chemistry would be a world which we cannot imagine, and we should all welcome and integrate the growth of chemical science into our material and moral worldview.

First published on the Scientific American Blog Network.

Macrocycle drug review

Here's a comprehensive and useful review of macrocycle drugs in J Med Chem by Giordanetto and Kihlberg at AstraZeneca; well worth reading to get an idea of what's out there in the clinic and on the market.

The authors looked at about 30 clinical macrocycle candidates and 70 marketed macrocycle drugs and analyzed their principal physicochemical properties to investigate trends and differences. Some main points emerging from the discussion:

1. Most macrocycles are in oncology or infection; however, the ones that are targeted toward other areas include a significant number of de-novo synthetic or semisynthetic molecules from structure-based drug design.

2. Among marketed macrocycles, injected drugs are mostly cyclic peptides while oral drugs are mostly macrolides (in general, injectable macrocycles seem to span a broader chemical space).

3. The structural differences between oral and injectable macrocycles can often be pretty trivial (at least on inspection; eg. tacrolimus vs pimecrolimus).

4. For oral macrocycles, increasing MW seems to track with increasing lipophilicity.

5. There's a set of plots which indicates the limits of chemical space within which marketed macrocycles seem to lie. "Rogue" rule-breakers like cyclosporin which lie very far from this space are still exceptions.

The question of whether we can deliberately engineer drug molecules to act like cyclosporin on a large scale is still very much an open one. What is clear is that we are increasingly making molecules that are decidedly testing the boundaries of the rule-of-5 and pushing the envelope. The future is not guaranteed, but it's promising.