Black clouds and silver linings: 2016 chemistry Nobel Laureate Fraser Stoddart's moving tribute to his wife

Sir Fraser Stoddart shared this year's Nobel Prize in chemistry for constructing tiny molecular machines based on the remarkable phenomenon of self-assembly, a process by which forces between atoms automatically pull diverse molecules together into precise geometric configurations without having to explicitly position them this way. These machines represent much promise for the field of nanotechnology, especially when we figure how to harness the mechanical forces in these molecules to perform specific functions like making copies of themselves, killing cancer cells or building other molecular materials. The Nobel Prize that Stoddart shared with fellow chemists Ben Feringa and Jean-Pierre Savage comes at the pinnacle of entire careers spent patiently exploring the structure and function of these molecular architectures.

One of the many interesting objects Stoddart created in the laboratory was a Borromean ring, a structure which had been mathematically conceived for some time but not physically realized until 2004 when Stoddart and his group chemically synthesized it. From a mathematical standpoint a Borromean ring is a good example of an object from the field of knot theory. It is a complex knot consisting of several interlocking rings. The special property of these rings is that you cannot cut any of them without having the entire structure break apart. From a chemical standpoint the Borromean ring is a tantalizing example of self-assembly, a process in which the individual molecules making up the ring simply 'find' each other and assemble; the chemist has to merely make the individual building blocks and find the right chemical conditions (solvent, temperature etc.) under which they can self-assemble.

The first molecular Borromean ring: 18 individual
molecules automatically self-assembly under the right conditions

Stoddart described the discovery of these Borromean rings in a talk given six years ago at the Institute for Human and Machine Cognition in Florida. The choice of the venue would be unusual were it not for the futuristic promise of molecular machines in improving human life, a goal also shared by the field of artificial intelligence. The entire talk is worth watching, but one part of the story which really stood out for me was a moving tribute by Stoddart to his wife Norma Stoddart who passed away from breast cancer in 2004. The tribute was not just moving but it also illustrated the classic yin and yang quality of life, with black clouds and silver linings. As Stoddart recounts, the breakthrough in designing the first Borromean ring was very much a sorely needed silver lining, not just because it came after a year of failures in deciphering the structure of these elusive molecules, but because it came at the end of receiving a tragic piece of news:

"It’s all part of life’s rich fashion. It’s not all a bowl of cherries. She was a brilliant scientist, much more able than I. She succumbed to breast cancer, and she fought that disease like no one’s business for 12 years.  She became known, ironically, as the little iron Englishwoman of Santa Monica. So that was Black Tuesday, it was the day that her oncologist said to me that the fight was over because the cancer had metastasized to her brain, and she always said that if that happened the fight would be over. So I came back to the lab from the clinic feeling quite low, and there was the structure of the Borromean Rings. So as they say, every black cloud has a silver lining."

Stoddart clearly enjoyed a very close relationship with his wife, and anyone who has lost a close spouse must know how incredibly hard and unique the pain is. Here's something that struck me: compared to the tragedy of losing a loved one, a specific scientific discovery might seem to provide negligible succor. And yet science has always been an amazing source of strength and certainty in tumultuous times, and this is one of its supremely important and reassuring qualities. Whether one is talking about European physicists finding refuge in the field of quantum mechanics during the politically fraught 1930s or, on a very personal level, a scientist finding refuge in the glow of scientific discovery in the shadow of a personal tragedy, this kind of novelty and joy in discovering new facts of nature is one of the things that makes science so much worthwhile. By recounting this moving story, Stoddart demonstrates not just the joy of science but its quintessential quality as a human endeavor. It is a triumph of the spirit over both scientific and personal hurdles. Thank you, Fraser Stoddart.

Note: Stuart Cantrill who got his PhD with Stoddart tells me that the first Borromean rings based on DNA were made by Nadrian Seeman of NYU. Stoddart and his team's, however, were the first rings based on small organic molecules. Here's a review on these fascinating objects which Stu pointed me to.

2016 Nobel Prize picks

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"). That's why every year you can carry over much of the same list of likely candidates as before.

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. Recent developments and a better understanding of scientific history also might make you add or subtract from your choices. For instance, last year the chemistry prize was awarded for the discovery of DNA repair systems, so that might make it a bit less likely for a biological discovery to be recognized this year. 

This time as in previous years, 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. Schreiber has already received the Wolf Prize this year so that improves his chances for the Nobel. The only glitch with this kind of recognition is that a lot of people contributed to the founding of chemical biology in the 1980s and 90s, so it might be a bit controversial to single out Schreiber and Schultz. The Thomson-Reuters website has a Schreiber prediction, but for rapamycin and mTOR; in my opinion that contribution, while noteworthy, would be too narrow and probably not sufficient for a prize.

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 very long time. Very few science-based innovations have revolutionized our basic standard of living the way lithium-ion batteries have. Generally speaking, recognition for the invention of specific devices have been rather rare, with the charged-coupled device (CCD) and the integrated circuit being exceptions. More importantly, a device prize was given out just two years ago in physics (for blue light-emitting diodes) so based on the Bayesian argument stated above, it might make it a bit unlikely for another device-based invention to win this year. Nonetheless, a prize for lithium ion batteries more than most other inventions would conform to the line in Alfred Nobel's will about the discovery that has "conferred the greatest benefits on mankind."

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. However, as often happens with the chemistry prize, this one could also go to medicine.

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. Hood has also been highlighted in the public eye recently through a new biography.

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 last year 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, which if anything seems to have become even more acrimonious since last year, reaching worthy-of-optioning-movie-rights level of acrimonious in fact. 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. A different way to look at the whole issue however is to say that the Nobel committee could actually heal the divisions by awarding the prize to the trio. Either way, a recognition of CRISPR is likely going to be one of the most publicly debated prizes of recent times.

It's also interesting to note that the folks at Thomson Reuters have cited only George Church and Feng Zhang in their picks. A prize only for the duo that leaves out the Berkeley scientists would likely ignite a bitter controversy that might make the controversy over the MRI prize pale in comparison. I don't think any kind of CRISPR recognition that cites only Church and Zhang would be good for the reputation of either the Nobel Prize or for science as a whole.

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, Leroy Hood 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. I have never really understood why he has never been recognized.

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.

The Thomson-Reuters team has cancer immunotherapy on their shortlist which I think is another good choice.

The physics prize: There is no doubt in my mind that this year's Nobel Prize in physics will be awarded to Kip Thorne, Rainer Weiss and Ron Drever for their decades-long dogged leadership and work that culminated in this year's breakthrough discovery of gravitational waves by the LIGO observatory. It's a dead ringer. Drever sadly suffers from dementia, but that certainly should not preclude the Nobel committee from honoring him. For those wanting to know more about the kind of dedication and personality clashes these three men brought to the project, Janna Levin's book which came out earlier this year is a great source.

There is another recognition that I have always thought has been due: a recognition of 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.

The Thomas-Reuters team predicts a chaos theory prize for the inventors of the OGY method. However it seems to me that a Nobel Prize for chaos theory and the study of dynamical systems - a field that surprisingly has not been recognized yet - should include any number of pioneers featured for instance in James Gleick's amazing book "Chaos", most notably Mitchell Feigenbaum.

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

Other predictions: Thomson-Reuters, artkqtarks, Everyday Scientist, In the Pipeline