What happens when chemists have nothing better to do on a Wednesday afternoon?

• This. It started with me posting a link on Facebook to an awesome recent paper describing physicists' efforts to reweigh the electron to an accuracy of one part in a trillion. The great Aaron Finke - of the regretfully dead Carbon-Based Curiosities - then weighed in.

   

  Aaron Finke This is what happens when physicists are bored.
  
  "So... uh... whatcha up to?"
  "Nothin, just Facebooking and eating a Hot Pocket"
  "...cool, cool. Wanna... wanna reweigh the electron?"
  "Yes. Yes I do."

  
  
• 

  Ashutosh Jogalekar Computational chemist version:
  
  "So…uh, whatcha up to?
  "Nothin, just twittering and eating a Hungry Man chicken meal."
  "…Cool…Hey, wanna parametrize that aziridine N-C bond with some stretch-bend cross-terms?
  "You bet!"

  
  
• 

  Ashutosh Jogalekar Synthetic chemist version:
  
  "So…uh, whatcha up to?
  "Nothin, just textin and eating an Amy's frozen teriyaki bowl." (clearly the synthetic chemist is more evolved)
  "…Cool…Hey, wanna repeat Woodward's B12 synthesis, but this time using RCM in some of the steps?"
  "Oh God yes!"

  
  
• 

  Aaron Finke Geologists:
  
  "So, uh, whatcha up to?"
  "Not much, just youtubing and eating taco bell"
  "Cool, cool. Hey, wanna get shitfaced?"
  "I already am"
  "Oh ok"

  
  
• 

  Ashutosh Jogalekar Clearly there's a fine line between being bored and being shitfaced.

  
  
• 

  Aaron Finke that's the nice thing about being a geologist
  
  you never have to be in a hurry

  
  
• 

  Ashutosh Jogalekar At least until the continents start coming together again. Then things get truly shitfaced in a hurry.

  
  
• 

  Aaron Finke "So, uh, whatcha up to?"
  "Nothin, just waiting for the continents to collide together again"
  "Cool, cool... how long will that take?"
  "Probably a couple hundred million years."
  "Cool, cool... wanna get shitfaced?"
  "I already am"
  "Okay"

  
  
• 

  Aaron Finke "Well, have fun. I'm gonna go help weigh that electron with the physicists"

  
  
• 

  Ashutosh Jogalekar *Geologist returns after helping physicists reweigh the electron, computational chemists parametrize every single molecule that can be built from 12 heavy atoms and synthetic chemists make vitamin B12 from a simple, four-carbon compound isolated from bat feces*
  
  "So, uh, whatcha up to?"
  "Nothin, just waiting for the continents to collide together again"
  "Cool, cool... how long will that take?"
  "Probably a couple hundred million years."
  "Cool, cool... wanna get shitfaced?"
  "I already am"
  "Okay"

  
  
• 

  Aaron Finke Why am I not a geologist

  
  
• 

  Ashutosh Jogalekar Because you would rather spend your time much more productively on the 67th synthesis of aquabatguanine using hammer and tong chemistry?

  
  
• 

  Aaron Finke what am I, Chinese?

  
  
• 

  Ashutosh Jogalekar Of course not. The Chinese made aquabatguanosine.

  
  
• 

  Aaron Finke ...again.
  
  well this might be the dumbest conversation on your FB wall ever. You're welcome.

  
  
• 

  Ashutosh Jogalekar Eminently postworthy (with your permission, naturally: I am planning to name it "When chemists have nothing to do on a Wednesday afternoon"). May even help to resurrect the dead CBC.

  
  
• 

  Aaron Finke do it

On making mistakes

In postulating an incorrect structure for DNA, Linus Pauling surprisingly committed an elementary chemical blunder (Image: pauling blog)

In the latest issue of the New York Review of Books, Freeman Dyson has a nice review of Mario Livio's readable book on scientific blunders committed by great scientists. The book is important reading for anyone who wants to understand the true history of science as a process of fits, starts, blind alleys, occasional great successes and of course, many blunders. Livio focuses on five famous scientists - Charles Darwin, Lord Kelvin, Linus Pauling, Fred Hoyle and Albert Einstein - who committed important mistakes. These mistakes sometimes set the field back but they also inspired other scientists to keep on looking and discovering new things. Scientists often build their theories and discoveries on the backs of other failed theories and discoveries. Just as respectable civilizations are often built on the bones of dead ones, respectable science is often built on the bones of scientific failures. And just like the natives are forgotten long after the settlers are celebrated, scientific failures get ignored at the expense of successes even when they are important in explaining the very existence of the successes.

Each of the blunderers in Livio's story blundered in a different manner. Darwin came up with a wrong theory of blending inheritance that he himself realized was acutely lacking in explaining real-world data. Mendel then discovered the right rules for inheritance and initiated a bonafide revolution in science. As Dyson explains, Mendel could improve on Darwin in no small part because he understood statistics and the law of averages better than the self-professed mathematically deficient Darwin. Lord Kelvin made his big blunder when he came up with wrong - and short - ages for both the sun and earth and thereby set up a significant obstacle to Darwin's theory of natural selection which demanded huge tracts of geological time to have passed for the evolution of species. The biological evidence was too overwhelming for Darwin to admit defeat but he clearly could not answer Kelvin's challenge. It was only in the middle part of the twentieth century when the fission and fusion processes powering radioactivity and the sun were worked out that Kelvin's question was posthumously addressed.

Fred Hoyle committed his major blunder and held on to a wrongheaded theory of the origin of the universe until his death. An early reason for Hoyle's recalcitrance in accepting the Big Bang was what he thought was the sheer audacity and fantasy of the theory, with the whole universe seemingly being conjured up from nothing in a flash. This aspect of Hoyle's thinking reminds me of Arthur Eddington's failure to take Subrahmanyan Chandrasekhar's theory of gravitational collapse seriously because he was convinced that there must be a law of nature preventing such a collapse. But the laws of nature are immune to our wishful thinking. The question of what came before the universe is still something that we grapple with, but every important discovery since the 1964 discovery of the cosmic microwave background has validated the Big Bang theory. Hoyle was certainly brilliant enough to have understood this evidence and he demonstrated his great scientific talents when he co-authored a seminal paper on nucleosynthesis with three other scientists. Hoyle thus stands as a curious example of someone who was in equal parts a reactionary and a maverick, not afraid to speculate on everything from extraterrestrial life to artificial intelligence but somehow never warming up to a revolutionary theory of the universe, even when it was supported by copious evidence.

Linus Pauling's mistake was of a different kind and rather hard to understand since it showed an embarrassing lack of knowledge of fundamental chemistry. Coming from someone widely considered to be the greatest chemist of the century this was odd, to say the least. After publishing his groundbreaking papers on the structure of proteins Pauling turned toward DNA and got embroiled in a race to decipher the structure of this all-important molecule with James Watson and Francis Crick. Although the race was perceived much more as such by the duo, Pauling certainly understood the importance of the problem. And then he famously committed an elementary chemical mistake. He published a paper in which the phosphates in DNA pointed inward and were held together by hydrogen bonds. Any good college chemistry student would know that at the pH inside the body (7.4) such hydrogen bonds would not exist and the oxygen atoms would be negatively charged, making them more likely to point outward into the ionic embrace of water. In his memorable book "The Double Helix", James Watson points out how his jaw dropped when he saw the mistake Pauling had made; ironically it was by consulting Pauling's classic "College Chemistry" textbook that he and Crick confirmed the error. As Watson put it, a graduate student under Pauling who made the same mistake would have probably been considered persona non grata at Caltech.

Why did the greatest chemist of the twentieth century miss such an elementary chemical fact about DNA? Even today the reasons are not completely clear. One reason could be that by the early 50s Pauling was much more concerned with nuclear disarmament than serious science, although he kept on publishing prolifically until his death. He could simply have been distracted from pursuing the DNA structure with the kind of full-time zeal that Watson and Crick did. The other reason is that he just missed the obvious. While this may sound surprising, it's a mistake that famous scientists who think out of the box can sometimes make. When it came to cracking the structure of proteins Pauling used a brilliant counter-intuitive approach. When it came to DNA the solution demanded a much more commonsense approach, and Pauling might have been still bogged down in protein structure for his mind to shift to this new kind of thinking. The last possible reason is also the most mundane; Pauling lacked the kind of high-quality structural data from x-ray diffraction that Watson and Crick got (some would say pilfered) from the technically accomplished Rosalind Franklin. When Watson saw the x-ray photographs he recalls feeling his pulse race, convinced that he had clinched it. Sometimes good data is all that separates a brilliant blunder from brilliant glory.

And then there's Albert Einstein whose brilliant blunder seems to indicate a lack of courage rather than a lack of scientific expertise. A lack of courage is another reason why scientists sometimes make important mistakes. In Einstein's case it was his injection of a fudge factor, the cosmological constant, to keep the universe static. Alexander Friedmann and Georges Lemaitre on the other hand had the courage to explore the logical solutions of Einstein's field equations, many of which pointed to an expanding and non-static universe. Einstein who had been a bold revolutionary when he came up with relativity turned out to be a conservative when clearly stating the possible consequences of relativity for the entire universe. In one sense this could be seen as the beginning of Einstein's reactionary streak, marking the time when he started opposing quantum mechanics and the picture of reality it presented. The ultimate irony of the fudge factor, as is now well known, is that it was resurrected by the discovery of the accelerating expansion of the universe and the postulation of dark energy.

As Dyson says, mistakes in science are essential, especially when you are exploring a new field on the cutting edge. No human mind is so all-knowing and perfect that it can cut through the fog of uncertainty and blunder to the solid heart of reality in one fell stroke. Especially at the beginning of a novel direction of research scientists should be liberally allowed to make mistakes. At the end of his review Dyson talks about a blunder he himself made pertaining to the incorrect prediction of the non-existence of charged weak bosons. He will probably agree that he has been so successful in science because he was allowed to make mistakes. Part of making mistakes is simply being able to generate lots of ideas; as one of the blunderers in Livio's book, Linus Pauling, put it, in order to have good ideas one must first have lots of ideas and then throw the bad ones away.

One of the most troubling casualties of the current climate of reduced science funding and flagging interest in science is that young scientists are afraid to make mistakes and therefore to generate lots of ideas. Funding agencies give them only a limited amount of money and ask them to work on "safe" problems; these are both constraints that reduce their appetite for risk-taking. Risk-taking has been one of the most important ingredients in the success of the United States as a leading scientific and technological power. Making mistakes is important not only in science but in business; think of how many computer, aircraft or skyscraper models were tried, tested and discarded before entrepreneurs came up with the correct ones. And it's a process that continues unabated. Once you ask a scientist to stop making mistakes you stop him or her from discovering. The stories of the scientists highlighted by Dyson and Livio as well as countless other episodes from the history of science make this fact clear. We ignore it at the risk of weakening the entire scientific enterprise.

First published on the Scientific American Blog Network.

Free online medicinal chemistry course at Davidson College

I wanted to alert interested readers to an introductory course on medicinal chemistry by Prof. Erland Stevens at Davidson College that seems to cover pretty much every basic and important aspect of drug discovery and medicinal chemistry that I can recall. 

As Prof. Stevens mentioned in an email, "The overall goal of the course is to get a student up to speed to watch a medicinal chemistry lecture (and maybe even ask a question at the end)." While the material may be a little too basic for readers of this (or Derek's) blog, it seems quite valuable for high-school or college students, and even for more experienced professionals who might want to brush up on their drug science.

The best part is that the course is free and available online.

Here's the website: https://www.edx.org/course/davidsonx/davidsonx-001x-medicinal-chemistry-1220

And here's the list of topics:

Week 1 – brief history of medicinal chemistry, introduction to drug development process and regulatory approval

Week 2 – proteins (enzymes and receptors) as drug targets, enzyme inhibition, ligand-receptor binding theory

Week 3 – pharmacokinetics (compartment models, Vd, clearance)

Week 4 – metabolism, phase I, phase II, prodrugs, genetic variability

Week 5 – drug-target complementarity, drugs as part of chemical space, chemical libraries

Week 6 – lead discovery, screening, filtering hits by metrics/structural alerts/predicted PK, SOSA, natural products

Week 7 – lead optimization, functional group replacements, isosteres, directed libraries, peptidomimetics

Syngenta, atrazine and keeping the science separate from the policy

The New Yorker has an excellent piece of reporting on the efforts of Tyrone Hayes, a UC Berkeley biology professor and his efforts to investigate potentially very important and deleterious effects of the herbicide atrazine on sexual dimorphism in frogs. In some of his experiments male frogs seemed to develop female genitalia. The major part of the piece is about how Syngenta - the maker of the multibillion dollar herbicide - tried to discredit Hayes. Ample supporting evidence is provided in internal memos and emails released as part of a law suit.

Many aspects of the story are worth thinking about but one of the most important ones is how such stories always risk the danger of conflating unethical behavior by companies with the underlying science. Syngenta shenanigans reported in the article are clearly unacceptable and stifling, but the message about atrazine is far more ambiguous. The piece points out several questions that the EPA raised about Hayes's studies (as well as Syngenta's), including proper statistical analysis and the extrapolation of amphibian studies to humans.

The important point is that these are valid and critical questions, even if Syngenta was using them to discredit Hayes (at one point one scientist dismisses statistical concerns as "routine", as if routine meant trivial). The motives of those wanting to use science to their own ends does not automatically affect the validity or lack therefore of the science itself. This is something that few environmentalists, in my experience, appreciate. Fortunately some do; for instance I have had commenters on my posts on GMOs explicitly saying that while they do support the science showing the safety of GMOs, they are much more concerned about the bullying and muzzling tactics used by companies like Monsanto. Sadly such commenters are precious and few.

The Syngenta/atrazine story falls in the same category. The company clearly used muzzling and shady tactics on Hayes but the verdict of atrazine's effects on human populations is clearly out there. In 2010 the EPA ruled out banning the herbicide for want of better evidence, and its decision only shows you how complicated it is to link the effect of any chemical to environmental or human damage. Personally - and I can't say I have reviewed the evidence in detail - I think Hayes is on to something but it's not certain exactly what.

I don't doubt that this article will spark furious allegations against Syngenta. But those who want to participate in this debate should keep something very simple in mind; science kowtows to no policy, even one designed to denigrate it. In your zeal to prosecute human being or corporations for unacceptable or criminal behavior, make sure that science does not become a casualty.

Atomic origin of the Bohr effect

Biochemistry. 2013 Nov 26;52(47):8539-55. doi: 10.1021/bi401126z. Epub 2013 Nov 13.

Hemoglobin Bohr effects: atomic origin of the histidine residue contributions.

Zheng G, Schaefer M, Karplus M.

Author information

Abstract

The Bohr effect in hemoglobin, which refers to the dependence of the oxygen affinity on the pH, plays an important role in its cooperativity and physiological function. The dominant contribution to the Bohr effect arises from the difference in the pKa values of His residues of the unliganded (deoxy) and liganded (carbonmonoxy) structures. Using recent high resolution structures, the residue pKa values corresponding to the two structures are calculated. The method is based on determining the electrostatic interactions between residues in the protein, relative to those of the residue in solution, by use of the linearized finite difference Poisson-Boltzmann equation and Monte Carlo sampling of protonation states. Given that good agreement is obtained with the available experimental values for the contribution of His residues in HbA to the Bohr effect, the calculated results are used to determine the atomic origin of the pKa shift between deoxy and carbonmonoxy HbA. The contributions to the pKa shift calculated by means of the linear response approximation show that the salt bridge involving His146 plays an important role in the alkaline Bohr effect, as suggested by Perutz but that other interactions are significant as well. A corresponding analysis is made for the contribution of His143 to the acid Bohr effect for which there is no proposed explanation. The method used is summarized and the program by which it is implemented is described in the Appendix .

Strolling in other fields

The lack of activity on this blog only means that I am spending all my time writing on my Scientific American blog, so I am just going to link to the posts there. One thing I am doing there is to write a user-friendly series on why drug discovery is so hard. Until now I have tackled target identification, hit identification and lead optimization and permeability. More to follow soon.

Why drugs are expensive: It’s the science, stupid.

Why drug discovery is hard – Part 2: Easter Island, Pit Vipers; Where do drugs come from?

Why drug discovery is hard – Part 3: Vacuum cleaners that make Sir James Dyson weep

Falsification and chemistry: What’s the rub?

Falsification and its discontents

“What scientific idea is ready for retirement?”

Vaclav Smil: “The great hope for a quick and sweeping transition to renewable energy is wishful thinking”

The many tragedies of Edward Teller

Should physicists stop looking for fundamental laws?

Physics and fundamental laws: Necessary truth or misleading cacophony?

Drugable.com "ranks billions of drug interactions"? Hold your horses.

Now here's a study that should make most seasoned molecular modelers cringe. Nature News reports on an effort by website Drugable.com that docked 600,000 compounds to 7,000 protein targets and predicted which ones would show activity against these targets based on docking scores:

Predicting how untested compounds will interact with proteins in the body, as Drugable attempts to do, is more challenging. In setting up the website, Cardozo’s group selected about 600,000 molecules from PubChem and the European Bioinformatics Institute’s ChEMBL, which together catalogue millions of publicly available compounds. The group evaluated how strongly these molecules would bind to 7,000 structural ‘pockets’ on human proteins also described in the databases. Computing giant Google awarded the researchers the equivalent of more than 100 million hours of processor time on its supercomputers for the mammoth effort.

But mammoth computing resources do not translate to carefully constructed protocols or correct predictions. In its current incarnation, docking is best for finding the binding pose, that is, the orientation of a drug bound into a protein pocket. Ranking compounds is far more difficult, and predicting absolute binding affinities is a very distant, currently unachievable third goal.

Anyone who has tried to run a hit to lead or lead optimization project based on docking scores would know how riddled with problems and qualifications any prediction based on these highly subjective numbers is. For starters, every modeling program gives you its own docking scores. Absolute values of these numbers (which ideally should reflect the free energy of binding but which seldom do) are almost always useless. If you are dealing with a congeneric series of molecules and are fairly confident about the binding orientation (usually confirmed by x-ray crystallography or some other technique) then maybe you could get some help from the scores in ranking the compounds, but even then mostly in terms of trends rather than quantitative differences.

Unfortunately the news piece says nothing about what method was used to generate the poses, whether there was any clustering or whether only the top pose was considered, what the false positive rate was, and most importantly, whether there was any experimental verification whatever of the ranking. The website is also not helpful in this regard. It also does not tell us if the protein structures used for docking were well-resolved or refined or whether they were homology models. In the absence of all this information the ranking of the compounds is tenuous at best and useless at worst and as it stands the study sounds little better than throwing darts in the dark and hoping some of them will stick. Ranking often fails even for similar compounds, so how well (or badly) it would work for 600,000 diverse compounds bound to 7,000 diverse protein targets is anyone's guess.

The report also compares the study to a similar activity prediction study by Brian Shoichet in which drug similarity was used to predict activity against unexpected targets. But that was a very different kettle of fish; it was a compound similarity - not docking - study so it did not have to deal with the complexities of error-ridden protein crystal structures or homology models, it verified a lot of the predictions using carefully constructed assays, and even then it gave a hit rate which did not exceed about 50%.

Either the Drugable.com study itself has failed to validate its predictions or the news report is woefully incomplete. Maybe I am wrong and in fact the study has laid the careful groundwork and validation that is necessary for trusting docking. As it stands however, the purpose of the report mainly seems to be to highlight the fact that Google generously donated 100 million hours of its computing power to the docking. This heightened, throw-technology-at-it sense of wonder and optimism is exactly what the field does not need. I would be the first one to welcome reliable predictions of drug-protein affinity based on wholesale docking of compounds to targets, but I don't think this work achieves that goal at all.

The future of nuclear energy: Let a thousand flowers bloom

The interior of a TRIGA nuclear reactor at Oregon State University (Image: Oregon State University)

In the summer of 1956, a handful of men gathered in a former little red schoolhouse in San Diego. These men were among the most imaginative scientists and engineers of their generation. There was their leader, Frederic de Hoffmann who had worked on the Manhattan Project and was now the president of the company General Atomics. Hoffmann was not only a creative physicist but also an unusually shrewd and capable manager and entrepreneur; in the later years of his life he would take the celebrated Salk Institute to great heights. There was also Freeman Dyson, a remarkably versatile mathematical physicist from the Institute for Advanced Study in Princeton who had previously reconciled disparate theories of quantum electrodynamics - the strange theory of light and matter. And there was Edward Teller, another Manhattan Project veteran; a dark, volatile and brilliant physicist who would become so convinced of the power of nuclear weapons to save the world that he would inspire the caricature of the mad scientist in Stanley Kubrick's classic film "Dr. Strangelove".

Together these men and their associates worked on a single goal: the creation of a nuclear reactor that was intrinsically safe, one that would cease and desist its nuclear transformations even in the face of human folly and stupidity. The reactor would have the rather uninspired name TRIGA (Training, Research, Isotopes, General Atomics) but its legacy would be anything but uninspiring. At the heart of the reactor's success was not a technical innovation but an open atmosphere of debate and discussion. Every day someone - mostly Teller - would come up with ten ideas, most of which sounded crazy. The others - mostly Dyson - would then patiently work through the ideas, discarding several of them, extracting the gems from the dross and giving them rigorous shape.

TRIGA benefited from a maximum of free inquiry and individual creativity and a minimum of bureaucratic interference. There was no overarching managerial body dictating the thoughts of the designers. Everyone was free to come up with any idea they thought of, and the job of the rest of the group was to either refine the idea and make it more rigorous and practical or discard it and move on to the next idea. The makers of TRIGA would have been right at home with the computer entrepreneurs of Silicon Valley a few decades later.

At the core of TRIGA's operation was a principle called the warm neutron principle. In a conventional reactor the neutrons in the fuel are moderated by hydrogen in the cooler water from the surroundings. There is a significant potential for a meltdown if someone pulls out the control rods, since the water which stays cool for a while will continue to moderate the neutrons and sustain their efficacy for causing fission. Dyson and Teller's idea was to place half of the hydrogen in the water and the rest in the fuel in the form of a uranium and zirconium hydride alloy. This would result in only half of the hydrogen staying cool enough to moderate the neutrons, while the other half in the hydride stays warm and diminishes the ability of the neutrons to fission uranium. This results in the fuel having what is called a negative temperature coefficient. The fuel rods were fashioned with care and precision by Massoud Simnad, an Iranian metallurgist working on the project.

The warm neutron principle is what made TRIGA intrinsically safe, very unlikely to sustain a meltdown or catastrophic failure. It took less than three years for the engineers and technicians to take the reactor from the design stage to manufacturing. The first TRIGA was inaugurated by none other than Niels Bohr in San Diego. Seventy of these safe reactors were built. They were safe and cheap enough to be operated in hospitals and universities by students and their main function was to produce isotopes for scientific and engineering experiments. They were also robust and safe enough to be proliferation resistant. As Dyson recounts in his elegant memoir "Disturbing the Universe", the TRIGA is perhaps the only nuclear reactor that made a profit for its creator.

TRIGA made the development of nuclear power seem relatively easy, cheap and fast. Why didn't other reactors enjoy the same success? Why, after fifty years, is nuclear power still struggling in the face of economics and political and social backlash? There are many reasons, but the principal reason is simple: the designers of TRIGA were encouraged to have fun and they had the kind of freedom of inquiry commonly found in a startup company. The problem is that the fun went out of the nuclear business in the 70s and with fun creativity and cost considerations also went out of the window. In his book Dyson swiftly cuts through to the central issue:

"The fundamental problem of the nuclear industry is not reactor safety, not waste disposal, not the dangers of nuclear proliferation, real though all these problems are. The fundamental problem of the industry is that nobody any longer has any fun building reactors....Sometime between 1960 and 1970 the fun went out of the business. The adventurers, the experimenters, the inventors, were driven out, and the accountants and managers took control. The accountants and managers decided that it was not cost effective to let bright people play with weird reactors. So the weird reactors disappeared and with them the chance of any radical improvement beyond our existing systems. We are left with a very small number of reactor types, each of them frozen into a huge bureaucratic organization, each of them in various ways technically unsatisfactory, each of them less safe than many possible alternative designs which have been discarded. Nobody builds reactors for fun anymore. The spirit of the little red schoolhouse is dead. That, in my opinion, is what went wrong with nuclear power."

Nobody builds reactors for fun anymore. What Dyson is getting at is quite simple. For any technological development to be possible, the technology needs to drive itself with the fuel of Darwinian innovation. It needs to generate all possible ideas - including the weird ones - and then fish out the best while ruthlessly weeding out the worst. This leads not only to quality but cost reduction since no entrepreneur is going to risk introducing an inherently expensive technology into the market. But all this is not possible until you allow people to play with ideas of their own volition and have fun doing it. People are not going to selflessly generate ideas by fiat, they are only going to do so when they are supported by funds and infrastructure but otherwise left to their own devices. The accountants and managers need to get the process started and then need to get out of the way.

Almost every successful technology has gone through this Darwinian phase. Dyson gives the example of motorcycles, which motorcyclists from his father's generation designed and serviced with care and affection. In our generation the most resounding example is that of computer technology. We have lost track of how many versions of software and hardware young computer enthusiasts experimented with in their California garages before their own technical and artistic sensibilities and the will of the market picked the best ones. Both Bill Gates and Steve Jobs made their fortunes in a milieu of young upstarts experimenting with the latest electronics and code and competing with fellow upstarts sprawled across the country. Just like the nuclear designers of the little red schoolhouse, the computer designers of the Silicon Valley garages were unencumbered by the demands of a central authority. So were the genetic engineers who founded companies like Genentech and Amgen. They could let their imaginations roam, bouncing ideas off one another and ruthlessly shooting down clumsy, expensive or ostentatious designs. It was the ability of bright young people to brainstorm to their hearts' content and to launch nimble startups rapidly exploring diverse and cheap technological solutions that allowed computer technology to become the all-pervasive life force that it is today. Biotechnology is now poised to do the same. A similar process of Darwinian survival of the fittest permeates other successful technologies, from flight to automobile engineering to house construction. And most importantly, the creators of all these technologies had fun creating them.

Nothing like this happened with nuclear power. It was a technology whose development was dictated by a few prominent government and military officials and large organizations and straitjacketed within narrow constraints. Most of the developers of nuclear technologies were staid, elderly bureaucrats rather than young iconoclasts like Frederic de Hoffmann. An early design invented by Admiral Hyman Rickover - suitable for submarines but hardly optimal for efficient land-based power stations - was frozen and applied to hundreds of reactors around the country. Since then there have been only a hundred or so reactor designs and only half a dozen or so prominent ones. Due to a complicated mix of factors including public paranoia, lack of economies of scale, political correctness and misunderstandings about radiation, nuclear technology was never given a chance to be played around with, to be entrusted to youthful entrepreneurs experimenting with ideas, to find its own way through the creative and destructive process of Darwinian evolution to a plateau of technological and economic efficiency. The result was that the field remained both scientifically narrow and expensive. Even today there are only a handful of companies building and operating most of the world's reactors.

To reinvigorate the promise of nuclear power to provide cheap energy to the world and combat climate change, the field needs to be infused with the same entrepreneurial spirit that pervaded the TRIGA design team and the Silicon Valley entrepreneurs. Young people who are brimming with ideas especially need to be given as many resources as possible to come up with solutions and explore them in startups, even if not garages. Just like any other technology, nuclear power can thrive only when the maximum number of people apply their creative minds to improving both the quality and cost of energy from fission. Fortunately a minority of companies and their creators are setting the trends.

I live in Cambridge, MA which has been a hotbed of innovation for several decades. In a few square miles along the picturesque Charles River lie literally hundreds of biotech, pharmaceutical and information technology startups, most enabled by the proximity of MIT and Harvard whose laboratories provide a steady supply of ideas that can be potentially turned into useful products. The scientists, engineers and managers in these startups constantly compete against each other and between themselves for the best ideas. My own startup is based on a novel way to make complex drugs using the specific base-pairing properties of DNA. Every year dozens of startups fail, and a few go public or are bought by other companies. The whole startup enterprise in Cambridge is subject to the forces of Darwinian selection that enables the filtering of the best ideas.

One component of this enterprise is named Transatomic Power. It was started by a duo of graduate students from MIT named Leslie Dewan and Mark Massie in 2010. The goal of Transatomic Power is to design a reactor that can generate power from nuclear waste, thus addressing the twin issues of clean energy and nuclear waste removal at the same time. The reactor which is a molten salt reactor lives off the preponderance of energy trapped in unfissioned reactor fuel from light water reactors. It is also compact enough to be shipped individually to the reactor site. Dewan and Massie are two of the few young people who actually see opportunity in the nuclear field and are willing to take risks in order to develop a novel approach to the problem.

On the other coast of the United States in Seattle is another team of nuclear entrepreneurs led by Nathan Myhrvold, a former CTO of Microsoft with degrees in physics and economics. Myhrvold has founded a company named Terrapower which operates on a novel nuclear design called the traveling wave reactor (TWR) which was also in part explored by Edward Teller and Lowell Wood in the 90s. The TWR is another reactor which can operate on waste, using depleted uranium to sustain a fission wave that spreads outward into the reactor, transforming the uranium into plutonium and leaving a small amount of fissile waste behind. The TWR promises to run for decades without having to refuel it or recover spent fuel, thus promising both safety and proliferation resistance. Among the enthusiasts of the TWR is Bill Gates, who knows a thing or two about Darwinian innovation in technology.

The founders of Terrapower and Transatomic are following in the footsteps of the dreamers in the little red schoolhouse. They have transformed nuclear technology into an entrepreneurial game of ideas and funding sustained by a healthy interplay between academic, industrial and government laboratories. I do not know whether their reactors will be the ones supplying the world's energy in the near future, but what I do know is that they are doing exactly what needs to be done to sustain the innovative process of creation and destruction that is necessary for the evolution of any successful technology. They are bucking the trend set by the large, bureaucratic government organizations and their industrial counterparts. And most importantly, they are having fun doing it, trading ideas and exploring new technical ground. I see hope in the adventures of these nuclear explorers, just like the makers of TRIGA saw hope in the future of nuclear power and the whole world saw hope in the explorers of computer and biotechnology in the 80s. When it comes to nuclear technology we should let a thousand flowers bloom. And then we can pick the most beautiful.

This post was first published on the Nobel Week Dialogue website.