Field of Science

The 2015 Medicine Nobel Prize is a tribute to drug discovery, chemistry and traditional medicine

It's very gratifying to see this year's Nobel Prize for Physiology or Medicine awarded to three scientists (William Campbell, Satoshi Omura and Youyou Tu) who have contributed to the discovery of novel drug substances that have decided benefited the lives of millions of human beings and animals. The prize was awarded to the discovery of avermectin and artemisinin. Avermectin cured nematode infections in millions of livestock animals including cows and pigs and its derivative ivermectin can cure river blindness, a disease primarily affecting poor people. Artemisinin can halt malaria in its tracks and contribute to substantial reduction of mortality.  It is hard to thing of a discovery which satisfies Alfred Nobel's stipulation of providing the "greatest benefit to mankind" more than this one. 

It's particularly gratifying to see pharmaceutical research being recognized with the prize. The last time the prize was awarded to drug discovery was in 1988, to Gertrude Elion and James Black. Both Black and Elion worked in the private sector. William Campbell who is one of this year's recipients also worked in the private sector at Merck in the 1980s when his team discovered avermectin. The strain of bacterium (Streptomyces) which yielded the drug had been discovered by Satoshi Omura's team in Tokyo. The collaboration was a perfect example of the public and the private sector working together to bring medical benefits to humanity. Campbell's team at Merck also discovered the even more potent derivative of avermetic, ivermectin, and this was discovered purely synthetically. It's also worth noting that Merck made avermectin available for free to treat river blindness in a generous gesture.

Youyou Tu's work on artemisinin in China during the 1960s is another lesson in pharmaceutical discovery. In the 1960s millions of poor Chinese were dying of malaria. The frontline drug, chloroquine, was being increasingly ineffective. Remarkably, Tu found an obscure reference to a document on traditional Chinese medicine written in 340 BC which described the potentially healing antimalarial powers of a herb steeped in cold water. By testing more than 200 extracts Tu discovered artemisinin. The initial paper in 1979 elicited skepticism and smug dismissal (partly because it came from communist China), but over the next thirty years artemisinin turned into a drug of choice for treating malaria.

Both artemisinin and avermectin exemplify the power of old-school chemistry and microbiology, a nexus blazed by antibiotic pioneers like Alexander Fleming and Selman Waksman, and one which has been largely forgotten in the last thirty years. In addition both compounds are natural products, and the prize underscores the value of drugs from nature (which already make up about fifty percent of all marketed drugs). Artemisinin in particular is also a vigorous validation of the potential of traditional Chinese (and other) medicine. This kind of medicine is completely different from homeopathy since it involves the use of actual chemical substances and herbal extracts. The story of artemisinin clearly indicates that we need to pay much more attention to forgotten examples from traditional Asian medicine and subject them to scrutiny.

Let's make no mistake about it: Today's Nobel Prize should thus be a resounding tribute to the power and humanity of pharmaceutical research. These days we are justifiably reluctant to associate that second adjective with anything to do with pharma; we are justifiably indignant at the price hikes, the off-label marketing and the other shenanigans which drug companies and CEOs sometimes indulge in. Yet this prize demonstrates that pharma, even Big Pharma, can do untold good, not just in discovery but in philanthropy. The distinguishing factors which characterized Merck in the 1980s were a strong focus on basic research (when my PhD advisor worked there during that time, people called it the "Merck University") and leadership under CEO Roy Vagelos - a rare, distinguished scientist at the helm who was a member of the National Academy of Sciences. Merck's success and largesse from the 1980s should be a role model for drug companies today- including Merck itself.

Interestingly, today's Nobel Prize is also great tribute to research which is decided non curiosity-driven and non-accidental. As this report on the discovery of avermectin from Campbell and his team says, "The discovery of the avermectin family of compounds was by no means serendipitous" (hat tip: Amanda Yarnell). I am as big a fan of curiosity-driven research as anyone else, but both avermectin and artemisinin were discovered with the express goal in mind of curing human disease. There is much to be said for this kind of deliberate applied research, supported by generous funding and vision at the top.

The recognition is also a tribute to the power of synthetic chemistry to create lifesaving substances that did not exist on earth before. Ivermectin is a purely synthetic derivative of avermectin created by using a chemical reaction (catalytic hydrogenation - itself awarded a chemistry Nobel Prize) that itself did not exist before.

So there it is: A Nobel Prize awarded to the benefits of private and public pharmaceutical research, awarded to the power of synthetic chemistry, awarded to the great potential of traditional medicine, and awarded to a female scientist. There's few Nobel Prizes that present such a happy constellation of qualities in one little package. Alfred Nobel would have been pleased.


George Whitesides to chemists: Move away from the molecule

This is an updated version of a post I wrote about an article by George Whitesides that exhorted chemists to move beyond the molecule. It was provoked in part by several recent discussions I have had about how chemists can have a broader impact on other disciplines as well as on the public appreciation of their own discipline.

Chemist George Whitesides probably does not consider himself a philosopher of chemistry, but he is rapidly turning into one with his thought-provoking pronouncements on the future of the field and its practitioners. His most recent rumination on the topic was a piece in the Annual Reviews of Analytical Chemistry provocatively titled "Is the Focus on Molecules Obsolete?" where he uses analytical chemistry as an excuse to really pontificate on the state and progress of chemical science. Along the way he also has some valuable words of advice for aspiring chemists.
Whitesides's main message to young chemists is to stop focusing on molecules. Given the nature of chemistry this advice may seem strange, even blasphemous. After all it's the molecule that has always been the heart and soul of chemical science. And for chemists, the focus on molecules has manifested itself through two important activities - structure determination and synthesis. The history of chemistry is essentially the history of finding out the structure of molecules and of developing new and efficient methods of making them. Putting these molecules to new uses is what underpins our modern world, but it was really a secondary goal for most of chemistry's history. Whitesides tells us that the focus of the world's foremost scientific problems is moving away from composition to use, from molecules to properties. Thus the new breed of chemists should really focus on creating properties rather on creating molecules. The vehicle for Whitesides's message is the science and art of analytical chemistry which has traditionally dealt with developing new instrumentation and methods for analyzing the structure and properties of molecules.
Of course, since properties depend on structures, Whitesides is not telling us to abandon our search for better, cleaner and more efficient techniques of synthesis. Rather, I see what he is saying as a kind of "platform independence". Let's take a minute to talk about platform independence. As the physicist Leo Kadanoff has demonstrated, you can build a computer by moving around 1s and 0s or by moving around buckets of water, with full buckets essentially representing 1s and empty ones representing 0s. Both models can give rise to computing. Just like 1s and 0s simply turn out to be convenient abstract moving parts for building computers, similarly a certain kind of molecule should be seen as no more than a convenient vehicle for creating a particular property. 
For practical applications that property can be anything from "better stability in whole blood" to "efficient capture of solar energy" to "tensile strength". The synthesis of whatever molecular material gives rise to particular properties is important, but it should be secondary; a convenient means to an end that can be easily replaced with another means. As an example from his own childhood, Whitesides describes a project carried out in his father's company in which his job was to determine the viscosities of different coal-tar blacks. The exact kind of coal-tar black was important, but what really counted was the property - viscosity - and not the molecular composition.
A focus on properties is accompanied by one on molecular systems instead of on individual moleculessince often it's a collection of different, diverse molecules rather than of a single type that gives rise to a desired property. What kind of problems will benefit from a molecular systems approach? Whitesides identifies four critical ones; health care, environmental management, national security and megacity management. We have already been living with the first three challenges, and the fourth one looms large on the horizon.
Firstly, health care. Right now most of the expenditure on health care, especially in the United States, is on end-of-life care. Preventative medicine and diagnostics are still relegated to the sidelines. One of the most important measures to drive down the cost of healthcare will be to focus on prevention, thus avoiding the expensive, all-out war that is often waged - and lost - on diseases like cancer during their end stages. Prevention and diagnostics are areas where chemistry can play key roles. We still lack methods that can quickly and comprehensively analyze disease markers in whole blood, and this is an area where analytical and other kinds of chemists can have a huge impact. And no method of diagnostics is going to be useful if it's not cheap, so it's obvious that chemistry will also have to struggle to minimize material cost, another goal which it has traditionally been good at addressing, especially in industry.
Secondly, the environment. We live in an age when the potentially devastating effects of climate change and biodiversity loss demand quick and comprehensive action. Included in this response will be the ability to monitor the environment, and to relate local monitoring parameters to global ones. Just like we still lack methods to analyze the composition of complex whole blood, we also lack methods to quickly analyze and compare the composition of the atmosphere, soil and seawater in different areas of the world. Analyzing heterogeneous systems with different phases like the atmosphere is a tricky and quintessentially chemical problem, and chemists have their work cut out in front of them to make such routine analysis a reality.
Thirdly, national security. Here chemists will face even greater challenges, since the solutions are as much political and social as they are scientific. Nonetheless, science will play an important role in the resolution of scores of challenges that have to be met to make the world more secure; these include quickly analyzing the composition of a suspicious liquid, solid or gas, unintrusively finding out whether a particular individual has spent time in certain volatile parts of the world or has been handling certain materials, and using techniques to track the movements of suspicious individuals in diverse locations. Chemistry will undoubtedly have to interface with other disciplines in addressing these problems and questions of privacy will be paramount, but there is little doubt that chemists have traditionally not participated much in such endeavors and need to step up to the plate in order to address what are obviously important security issues.
Fourthly, megacities. As we pick up speed and move into the second decade of the twenty-first century, one of the greatest social challenges confronting us is how to have very large, heterogeneous populations ranging across diverse levels of income and standards of living co-existing in peace over vast stretches of land. This is the vision of the megacity whose first stirrings we are already witnessing around the world. Among the problems that megacities will encounter will be monitoring air, water and food quality (vida supra). A task like analyzing the multiple complex components of waste effluent, preferably with a readout that quantifies each component and assesses basic qualities like carcinogenicity would be invaluable. There is no doubt that chemists could play an indispensable role in meeting such challenges.
The above discussion of major challenges makes Whitesides's words about moving away from the molecule clear. The problems encompassing health care, national security and environmental and megacity management involve molecules, but what they really are are collages resulting from the interaction of molecules with other scientific entities, and with the interaction of chemists with many other kinds of professional scientists and policy makers. In one sense Whitesides is simply asking chemists to leave the familiar environment of their provincial roots and diversify. What chemists really need to think of is molecules embedded in a broad context involving other disciplines and human problems.
Part of the challenge of addressing the above issues will be the proper training of chemists. The intersection of chemistry with social issues and public policy demands interdisciplinary and general skills, and Whitesides urges chemists to be trained in general areas rather than specialized subfields. Courses in applied mathematics and statistics, public policy, urban planning, healthcare management and environmental engineering are traditionally missing from chemistry curricula, and chemists should branch out and take as many of these as is possible within a demanding academic environment. It is no longer sufficient for chemists to limit themselves to analysis and synthesis if they want to address society's most pressing problems. And at the end of it they need not feel that a movement away from the molecule is tantamount to abandoning the molecule; rather it is an opportunity to press the molecule into interacting with the human world on a canvas bigger than ever before.

Identical ligands, unrelated proteins, similar energies - When language collides with the facts of nature

Recognition of aromatic rings by two very different
mechanisms but through similar binding energies
Over the years chemists have come up with many different ways to talk about the structure and energetics of molecules and especially to compare these parameters between various compounds. Doing this comparison is not just an academic exercise; for example, knowing which drug molecules are ‘similar’ or ‘different’ can be the deciding factor in picking one drug over another. It is also crucial for knowing the kinds of side effects that drugs can induce by interacting with off-target proteins.

Unfortunately the application of these simple descriptions to matters of molecular description is a very good example of what happens when language collides with fuzzy, ill-defined facts in nature. ‘Similarity’ is a classic example. When you are talking about two drugs being similar for instance, are you talking about their similarity purely in terms of molecular structure (which itself can be defined in many different ways), or their similarity in terms of their effects on cancer cells, or their similarity to engage a common protein target in the body, or through similar side effects? Clearly there are many different ways to define similarity and all these ways are subjective to a large extent.

But there is a problem with applying language to chemical concepts even at a very limited and basic level. A great example of this conundrum is hinted at by a paper from Brian Shoichet’s group at UCSF that just came out in the journal ACS Chemical Biology. The paper asks a very fundamental question: Do identical small molecules or ligands bind to very different proteins? The question in fact goes deeper: How do you define similarity and differences between various proteins to begin with?

To investigate this question, the authors consider 59 ligands bound to 119 different proteins in the PDB. Many bind with high affinity, ranging from low nanomolar to mid micromolar. What the study does is to classify these protein-ligand pairs into three groups. The first group consists of pairs in which the same atoms in identical ligands bind to similar or identical residues in different proteins. The second group consists of the same ligand atoms in identical ligands binding to similar kinds of residues (hydrophobic, positively charged etc.). The third group in a sense is the most interesting since it involves identical ligands binding to completely different proteins; in these cases the binding involves neither similar ligand atoms nor similar protein environments.

The authors find that a good two thirds of the set of protein-ligand pairs involve identical ligands binding to proteins with dissimilar residues. In addition, half of these involve ligands binding to proteins with completely different environments. There is thus no ‘pattern-matching code’ for the same ligand binding to different proteins.

Why do identical ligands bind in very different protein environments? The simple reason is because chemical binding is to a large extent a non-specific process, and there are many ways to skin the protein-ligand cat. Hydrophobic groups bump into hydrophobic groups, positively charged groups interact with negative charged ones and polar atoms snuggle up against other polar atoms. As the authors say:
"A reason why there is no simple code for ligand recognition among binding sites is that proteins have found multiple, at least superficially unrelated ways to recognize most common ligand groups. Thus, cationic amines can be recognized both by anionic residues such as aspartate or glutamate, but they can also be recognized by cation-Pi interactions. Nucleotide phosphates can be recognized by cationic residues such as arginines, but recognition by main chain amide nitrogens in a P-loop is also common. Ligand aromatic groups can stack with tyrosines, phenylalanines and tryptophans, but they can also form cation-Pi interactions many other variations might be mentioned."
But sometimes hydrophobic groups can also snuggle up against polar atoms or poke out into solvent and polar groups can nestle into hydrophobic pockets to various extents, simply because the other atoms in the ligand compensate for such uneasy alliances by forming favorable interactions. This can lead to the same ligands binding to very different protein atoms. As I mentioned in a previous post, atoms end up somewhere simply because they can. The differential placement of atoms in protein pockets is reflected in the different binding affinities that the authors see in their set.

From an evolutionary viewpoint this observation is very interesting. Protein-small molecule binding was constrained during evolution by the basic chemistry and physics of binding on one hand and by the damage incurred by too much non-specific binding on the other (as an extreme case, if every small molecule bound to every protein, there would be way too much noise and biological signaling networks would be effectively impossible). Thus there had to be a balance between promiscuity and specificity. Nature achieved this balance by tuning the affinity of small molecules for proteins over a wide range and by making sure that even weak affinity could translate to significant biological effects.

Unfortunately these are precisely the affinities that we ourselves want to finely tune in a drug discovery program and as the paper shows, this is always going to be an uphill battle because of the multitude of interactions and the lack of correlation between ligand and binding pocket structure (one conclusion from the paper is that you cannot always predict new targets for known ligands simply by computationally comparing binding sites).

But on another level I think this problem also speaks to the paucity of the language that we have for describing binding affinity and molecular interactions in general. Our metric for similarity in this case is the presence of similar ligand atoms binding to similar protein atoms. But nature can use another very simple measure of similarity – similarity in binding energy. It is not unreasonable to say that a ligand binds similarly to two proteins if it exhibits a similar binding affinity to both of them. And this binding affinity need not even be very different since even a few kcal/mol difference in binding energy can translate to a thousand fold difference in actual affinity (say from micromolar to nanomolar). Thus, what we call dissimilar binding may actually be judged as quite similar by nature. Consider the picture at the top of the post for instance: an aromatic ring can interact with a protein through either a stacking interaction with an aromatic amino acid or through a cation-pi interaction with a positively charged amino acid. The two interactions look very different, and yet they involve the same binding affinity. 

All this goes back to something we mentioned before: Similarity is in the eye of the beholder, and what our eye sees as squiggly lines of ligands and protein residues on a computer screen, nature sees simply as thermodynamics, kinetics and quantum mechanics, and all of it lying on a continuum. We might be dismayed to know that the same ligand is binding to very different proteins, but this is because nature may not be regarding them as very different to begin with. To figure out protein-ligand binding then, we may have to see things from the point of view of nature rather than that of our impoverished language.

2015 Nobel Prize predictions

The nice thing about Nobel Prizes is that it gets easier to predict them every year, simply because most of the people you nominate don't win and automatically become candidates for the next year (note however that I said "easier to predict", not "easier to correctly predict").

Having said that, there is a Bayesian quality to the predictions since the previous year's prize does compel you to tweak your priors, even if ever so slightly. Last year's award was for a biophysical instrumental technique so that probably rules out similar awards this year. 

This year I have decided to separate the prizes into lifetime achievement awards and specific discoveries. There have been fewer of the former in Nobel history and I have only three in mind myself, although the ones that do stand out are no lightweights - for instance R B Woodward, E J Corey, Linus Pauling and Martin Karplus were all lifetime achievement awardees. If you had to place a bet though, then statistically speaking you would bet on specific discoveries since there have been many more of these. So here goes:

Lifetime achievement awards

Harry Gray and Steve Lippard: For their pioneering and foundational work in the field of bioinorganic chemistry; work which has illuminated the workings of untold number of enzymatic and biological processes including electron transfer.

Stuart Schreiber and Peter Schultz: For their founding of the field of modern chemical genetics and their impact on the various ramifications of this field in chemistry, biology and medicine.

Robert Langer for his extensive contributions to drug delivery: Much of what Langer does is actually chemistry, but his practical impact has been on medicine so a prize for him would lie more squarely in medicine. It's clear though that he deserves some kind of lifetime recognition.

Specific awards

John Goodenough and Stanley Whittingham for lithium-ion batteries: This has been on my list for a long time. Very few science-based innovations have revolutionized our basic standard of living the way lithium-ion batteries have. However, prizes for devices have been few, with the charged-coupled device (CCD) and the integrated circuit being exceptions. More importantly, a device prize was given out just last year in physics (for blue light-emitting diodes) so based on that Bayesian argument stated above, it might make it a bit unlikely for another device-based invention to win this year.

Franz-Ulrich Hartl and Arthur Harwich for their discovery of chaperones: This is clearly a discovery which has had a huge impact on our understanding of both basic biological processes as well as their therapeutic relevance. I worked a bit on nuclear receptors myself during a postdoc and appreciate the amazing complexity and importance of their signaling roles. However, as often happens with the chemistry prize, this one could also go to medicine.

Alexander Pines for solid-state NMR: Another technique that has clearly come of age. Using our Bayesian ruler again though, last year's chemistry prize went to an instrumental technique (super-resolution electron microscopy) so it seems implausible to have the same type of prize given out this year.

Krzysztof Matyjaszewski for atom-transfer radical polymerization, Barry Sharpless for click chemistry, Chi-Huey Wong for oligosaccharide synthesis and Marvin Caruthers for DNA synthesis: It's highly unlikely that these three gentlemen will receive any prize together, but I am grouping them under the general title of "organic and polymer synthesis" for convenience.

Matyjaszewski's name has been tossed around for a while, and while I am no expert in the field it seems that his ATRP method has had enough of a practical and commonplace impact to be a serious contender; plus an award for polymer chemistry has been long due. Click chemistry has also been extensively applied, although I am less certain of its industrial use compared to say, the undoubted applications of palladium-catalyzed chemical reactions.

In the world of biopolymers, oligosaccharide synthesis has always been an important field which in my opinion has received the short end of the stick (compared to the glamorous world of proteins and nucleic acids, lipids and carbohydrates have always been the black sheep) so recognizing Wong might be a kind of redemption. On the other hand, recognizing Caruthers for DNA synthesis (perhaps along with Leroy Hood who automated the process) seems to be an obvious honor in the Age of Genomics.

The medicine prize

As is traditionally the case, several of the above discoveries and inventions can be contenders for the medicine prize. However we have left out what is potentially the biggest contender of all until now.

Jennifer Doudna, Emmanuelle Charpentier and Feng Zhang for CRISP-Cas9: I don't think there is a reasonable soul who thinks CRISPR-Cas9 does not deserve a Nobel Prize. In terms of revolutionary impact and ubiquitous use it almost certainly belongs in the same shelf that houses PCR and Sanger sequencing. 

There are two sets of questions I have about it though: Firstly, whether an award for it would still be rather premature. While there is no doubt as to the broad applicability of CRISPR, it also seems to me that it's rather hard right now to apply it with complete confidence to a wide variety of systems. I haven't seen numbers describing the percentage of times that CRISPR works reliably, and one would think that kind of statistics would be important for anyone wanting to reach an informed decision on the matter (I would be happy to have someone point me to such numbers). While that infamous Chinese embryo study that made the headlines recently was quite flawed, it also exposed the problems with efficacy and specificity that still bedevil CRISPR (these are problems similar to the two major problems for drugs). My personal take on it is that we might have to wait for just a few more years before the technique becomes robust and reliable enough to thoroughly enter the realm of reality from one of possibility.

The second question I have about it is the whole patent controversy. Generally speaking Nobel Prizes try to stay clear of controversy, and one would think that the Nobel committee would be especially averse to sullying their hands with a commercial one. The lack of clear assignment of priority that is being played out in the courts right now not only tarnishes the intellectual purity of the discovery, but on a more practical level it also makes the decision to award the prize to all three major contenders (Doudna, Charpentier and Zhang) difficult. Hopefully, as would be fitting for a good novel, the allure of a Nobel Prize would make the three protagonists reach an agreement to settle their differences over a few beers. But that could still take some time.

The bottom line in my mind: CRISPR definitely deserves a prize, and its past results and tremendous future potential may very well tip the balance this year, but it could also happen that the lack of robust, public vindication of the method and the patent controversy could make the recognition seem premature and delay the actual award.

Craig Venter, Francis Collins, Eric Lander and others for genomics and sequencing: The split here may be pretty hard here and they might have to rope in a few consortiums, but as incomplete and even misleading as the sequencing of the human genome might have been, there is little doubt that it was a signal scientific achievement deserving of a Nobel Prize.

Alec Jeffreys for DNA fingerprinting and assorted applications: Alec Jeffreys is another perpetual favorite on the list and one whose invention has had a huge societal impact.

Karl Deisseroth, Ed Boyden and others for optogenetics: Optogenetics is another invention that will almost certainly get a prize; its methodology is fascinating and its potential applications for neuroscience are amazing. But its validation seems even more incomplete to me than CRISPR's so it would be rather stunning if they get the prize this year. (On a side note: I am probably among the minority who think that awarding the prize for RNA interference in the 1990s was also too early and quite premature).

Ronald Evans for nuclear receptors: It would be odd if a major class of proteins and therapeutic drug targets went unrecognized.

Bert Vogelstein, Robert Weinberg and others for cancer genes: This again seems like a no-brainer to me. Several medicine prizes have been awarded to cancer genetics so this certainly wouldn't be a novel idea, and it's also clear that Vogelstein and Weinberg have done more than almost anyone else in identifying rogue cancer genes and their key roles in health and disease.

A brief note on the physics prize: There is no doubt in my mind that the Nobel committee needs to give the prize this year to the ATLAS-CMS collaboration at the LHC which discovered the Higgs boson. A prize for them would emphasize several things: it would put experiment at the center of this important scientific discovery (there would have been no 2013 Nobel Prize without the LHC) and it would herald a new and necessary tradition of awarding the prize to teams rather than individuals, reflecting the reality of contemporary science.

So that's it from my side. Let the games commence!

Note: Reader artqtarks has a list, with a thoughtful analysis of potential prizes for CRISPR and tumorigenic genes.

3 Quarks Daily annual science writing prize

I am honored and frankly a bit stunned to hear that my post on the "fundamental philosophical dilemma" of chemistry was awarded first place in the annual 3 Quarks Daily science writing prize contest. I am deeply thankful to the editors of the site, to those who nominated the post and to Prof. Nick Lane who judged the final nine entries.

I am enormously gratified that my entry was selected by Nick Lane, biochemist and science writer extraordinaire, whose latest book "The Vital Question" proposes a novel theory of the origins of life based on the genesis and evolution of the energy generating apparatus in cells. I have long since admired Nick's books both for their originality and their clarity so I was especially thrilled that he picked my post. And I am stunned because my entry was included in a roster of entries that included some very fine writing indeed by writers whose work I have respected for a long time, so I didn't expect my own entry to win. Congratulations especially to my fellow prizewinners, Aatish Bhatia and Nadia Drake, for their incisive and highly readable pieces. The list of finalists is also very much worth taking a look at.

Here's what Nick had to say about the post and about his own views on writing:

When I read a blog, I'm not really looking for a beautiful piece of writing, or stunning visuals, or links to amazing videos, even though these things make a great post. I'm looking for a personal point of view, usually from someone with a particular vantage point, whether scientific or journalistic. I'm looking for something that I couldn't find so easily in the mainstream media, grounded in personal experience, and more idiosyncratic than most magazines would allow you to get away with. (That's one of the things I like about writing books too.)

I don't really know where to draw the line between a blog and a news story, or a feature article, or even a short story. Some of the finalists here did not really write blog posts at all, in my view, but achieved a higher calling, works of art in their own right. So with all that in mind, here goes:

The winner is Ashutosh (Ash) Jogalekar. I loved this post. It is personal and authoritative, and grows from what starts out as a quirky irritation in the day job into a profound commentary on the limits of the controlled experiment in chemistry, stemming from fundamental physics. Ash begins with the different interactions between atoms in molecules – electrical charges, hydrophobic interactions and the rest – and shows them to be different aspects of the same fundamental electrochemical force, making it impossible to achieve any independent changes in a molecule. He finishes with a lovely twist, justifying the thrill of experiment as the only way to explore design in chemistry, making the subject endlessly fascinating. 

Ash's writing style is crisp and clean, admirably precise without being patronising, even in the use of italics, which can easily feel preachy. Not here. I followed the links for genuine interest, and there was a great discussion in the comments pointing out an equivalent problem in biology, in the use of knockout models. In an age when science is being pushed towards supposedly managed outcomes, this is a refreshing reminder of why it can't be planned.

Many thanks to Nick for his very thoughtful appraisal and appreciation of the piece. I am especially thrilled to see writing about fundamental chemistry - a topic that doesn't usually get much billing in the popular science literature - being recognized. The limits of performing controlled experiments in science is a topic close to my heart, and I'm glad to see that others have thoroughly appreciated the problem too. 

Occasionally we'll hear drumbeats about the "end of science" which proclaim the complete ascendancy of knowledge in one field or another. While this kind of proclamation ignores the simple fact that progress in different fields is not all created equal (as a commenter on a blog recently mentioned, "we can land a probe on a comet at 17,000 miles/hr but we still don't know if butter's bad for you") I think it's also important to realize more fundamental, epistemological limits to knowledge that arise from the kinds of limits on measuring basic atomic and molecular interactions that I was talking about in my post. 

But crucially, while some may see such limits as heralding "the end", I see them as heralding endless opportunities and fascinating discoveries which will forever remain open-ended. If that's not the opposite of "the end" I don't know what is.

Agonists and antagonists, and why drug discovery is hard (again)

Here's a valuable and comprehensive review on one of the most glaring pieces of evidence for why drug discovery is so hard - the fact that very small structural changes in molecules can lead to drastic changes in their biological activity.

I particularly like this review because it's absolutely chock-full of examples of small structural changes which not only impact the magnitude of binding of a small molecule to a receptor protein but invert it - that is, change an agonist into an antagonist. And the receptor family in this case is GPCRs, so it's not like we're talking about a minor rash of examples in a scientifically insignificant and financially paltry domain.

Here's one of my favorite examples from the dozens showcased in the piece; in this case a set of small molecules targeting the nociceptin receptor which is being studied as a potential target in treating heart failure and depression.

At first sight it's compelling how such similar groups as a cyclooctyl, a cyclooctyl-methyl and a phenyl can lead to complete inversion of activity, from 200 nM agonism to 1.5 nM antagonism. Thinking in 3D however makes the observation a bit more comprehensible. The N-cyclooctyl on the right is going to have a very well-defined conformational preference - pointing pretty much straight in one direction. The cyclooctyl-methyl on the other hand is going to have much more conformational freedom. It's also going to occupy much more space than the phenyl group on the right.

Now this kind of retrospective analysis may well be the explanation, but very few medicinal chemists would have been able to predictive this complete inversion in activity at the outset (as a medicinal chemist recently quipped at a Gordon Conference, "We medicinal chemists are very good at predicting the past.")

Here's a more diabolical example that would have been even harder to predict. In this case the target concerns two suptypes of the mGlu (metabotropic glutamate) receptor which is involved among other things in Parkinson's and anxiety.

In this case, not only does that 'magic' methyl group and its precise stereochemistry change an antagonist into an agonist but it even changes the agonism/antagonism mix at two separate receptors. Try explaining that, even in retrospect.

These kinds of well-known activity cliffs reinforce the essentially non-linear nature of medicinal chemistry, a quality that is essentially emergent since it arises from the interaction of small molecules with a highly non-linear biological system. Neither experimental chemistry nor computational modeling would allow us to predict activity cliffs like these because of the lack of sensitivity in such techniques.

It's things like these which I always think really need to be communicated to laymen to impress the staggering difficulty of drug design to them - most of the times we are simply ignorant when it comes to designing molecules like the ones above with any kind of predictive power and we can only find out about their fickle properties in retrospect. Perhaps then we will get less heat from the public for why we sometimes have to spend (and charge) so much money for our products.

Prof. Erland Stevens's edX med chem class

Just as he did previously, Prof. Erland Stevens of Davidson College is teaching a comprehensive med chem edX class that would be useful for anyone wanting to dive into the field. The course attracted 25,000 students last year. Here's the syllabus and list of topics - it certainly looks like something I would enthusiastically check out if I were starting out in the field, or even if I had been in it for a while.

Information on the course:

  • The course: D001x Medicinal Chemistry
  • Host platform: edX
  • Date: Starts 10/5/15, but enrollment is open until 12/11/15
  • Length: 8 weeks
  • Cost: free
  • Time: 6-8 h/wk for all content, 1 h/wk to peruse the video lectures
  • Pre-req: chem (organic functional groups, line-angle structures), biology (parts of cell), math (logarithms & exponents)
  • Topics (~1 wk per topic)
  • Drug Approval (early drugs, regulatory process, cost, IP concerns)
  • Enzymes & Receptors (inhibition, Ki, ligand types, Kd)
  • Pharmacokinetics (Vd, clearance, compartment models)
  • Metabolism (phase I & II reactions, CYP450 isoforms, prodrugs)
  • Molecular Diversity (binding, drug space, combi chem, libraries)
  • Lead Discovery (screening, filtering hits, drug metrics)
  • Lead Optimization (functional group replacements, isosteres, peptidomimetics)
  • Case Studies on Selected Drug Classes
  • Bonus features
  • Interviews with pharma professionals, including scientists from Novartis (a partner on the course)
  • Virtual labs involving online tools for predicting drug-relevant activity
  • Target audience: pre-med students, graduate students, recent pharma hires, research assistants