No, I didn't build it myself, but....

I just delivered the Karcher Lecture at the University of Oklahoma. People call this university OU and not UO. [I wondered if this was  to avoid  students saying "I go to the University of Oklahoma" and being subjected to the smug retort: "Ah, You Owe!" But, I digress :-)]. Karcher discovered reflection seismography  when working for NIST, used these to discover oil, then co-founded what became Texas Instruments.  Texas Instruments is where Jack Kilby worked when he invented the integrated circuit, the basis of computer hardware. He won the 2000 Physics Nobel for that. I liked Kilby's Nobel lecture in which he stated how he felt when he saw a computer: 'It's like the beaver told the rabbit as they stared at the Hoover Dam. "No, I didn't build it myself, but it's based on my idea."'

Nobel Prize in Chemistry

The Nobel Prize in Chemistry was today awarded to my postdoc advisor, Martin Karplus (above) together with Michael Levitt and Arieh Warshel. These are three of the main developers of our field of biomolecular simulation. This announcement was somewhat a surprise as this field had not been a favourite in the "betting". Also,  there are several other scientists in the field who, in my opinion, have made comparably strong overall contributions. However, what the three winners played leading roles  in in the 1970s was certainly special -  the genesis of biomolecular simulation.  Scientists had before that time already been deriving spectroscopic force fields, to match infrared and Raman frequencies, but these don't provide information on structural energetics. Also, others had been working on molecular mechanics force fields and methods to find energy-minimum conformations of organic molecules and peptides. The three winners, inspired by Lifson in Israel, were at the origin of many of the ideas that have slowly blossomed into the present-day biomolecular simulation field, in all its glory, with molecular dynamics simulations of biomacromolecules, QM/MM calculations of reaction rates (which, perhaps surprisingly, was the sole subject of the Nobel citation), protein folding calculations, free energy analyses, the design of drugs currently on the market,  and everything else.

All three of the winners have had to endure heavy professional criticism from different parts over the years. Our field was frowned upon by many for a long time. Many of the calculations performed were, and are, wrong, inconsistent, biased and disagree with experiment and these shortcomings were jumped upon by discreditors and still are, although to a lesser extent, nowadays. However, the three Laureates certainly got everyone's attention early on. I don't know Michael Levitt personally so well, but of course I know his work. In the 1970s and 1980s, working in Cambridge, he published papers folding BPTI and predicting protein stability that created quite a storm. Arieh Warshel was at the origin of some of the key concepts in the field - I would think of his multiple papers on the electrostatic control of enzyme reactions. As for Martin, he's been absolutely towering. Carefully building up the complexity of the systems he studied, from simple hydrogen reactions through conformational NMR to large biological complexes, his contributions have been wide-ranging, careful, and thorough. His QM/MM work was but a small part of his overall career.

As ever in human life, the strongest reflections at these times are maybe personal. Michael Levitt impressed me by working mostly alone for a long time, when everyone else was building up large groups. Many of us know the twinkle in Arieh Warshel's eye when he stands up in a conference and criticizes the speaker, and we can all recognize his 'anonymous' referee reports. As for Martin, he has left an indelible impression on all of us who have passed through his lab over the last 50 years. He's has been a dedicated servant to science - a role model for us all. Congratulations to all three - and to my ex-boss in particular!

And When They're 45?

I'm currently at a workshop in Lausanne, Switzerland and one of the lecturers is Dorothee Kern from Brandeis University. She was point guard in the East German National Basketball team in the 1980s and has kept playing, leading the German National Over-45s to winning the world championships this year. I asked her about the USA team. Given that they're so good at college, how did they do? Dorothee answered that they didn't even have a team.

This is sad, but jives with my experience of adults doing sports in the USA. They are active at school, jamming the soccer fields with kids playing soccer under the adoring eyes of parents, but by the age of 20 everything has stopped. Inactivity, indolence, unhealthy obesity.

The next Master's World Basketball championships is in Orlando, sponsored by ESPN. Maybe the USA won;t have a team there, either?

Accidental Nuclear Holocaust over North Carolina?

A newly declassified report from Sandia National Laboratory confirms that in 1961  B-52 broke apart over North Carolina dropping two 4 megaton bombs. One fell to the ground unarmed. But the second assumed it was being deliberately released over an enemy target - and went through all its six arming mechanisms save one. OK - that's certainly scary. But how scary exactly? The journalist currently publicizing this states  "only the failure of a single low-voltage switch prevented disaster".  In contrast, the declassified report states that a short would have been required i.e. the sixth switch appeared to function as it should have.  How close were we actually? In nearly 70 years we haven't had a single nuclear weapon accidentally detonated, but we need to be careful that it never happens in the future.  

My future job

Mr. Neil Doncaster,

Chief Executive,

Norwich City Football Club,

Carrow Road

Norwich NR2 3EW

Dear Neil,

After the debacles against Hull and Spurs, whereby in both games the lads managed to reduce themselves within 5 minutes to lurching after the shadows of the opposition like blinded zombies, it’s clear that Carrow Road needs some big changes.

So I am hereby applying for the obviously-soon-to-be-vacant position of manager of Norwich City FC.

You’ll probably want to know what experience I have in running a football club? The answer is: none whatsoever!

So what? I’ll run the show using a three-point principle broadly inspired by the athletics department of my current employer.

Firstly, I’ll get rid of the best players. This will engender an unprecedented level of solidarity in the remainder, leading to their being psychologically solidly impenetrable.

Anyway it’ll be quite easy to do because my predecessor Hughton has already voided the club of all but a couple of the good players – there’s only Hoolahan and the lad Redmond left. They’ll have to go!

Secondly, in a revolutionary step, I’ll remove the goalkeeper from the team! Knowing that our goal is gaping and unprotected will give our outfield players tremendous incentive to never let the opposition have the ball.

Thirdly, I’ll stop all training sessions. This will make the players so keen to play so that, come Saturday afternoon they’ll all run around like demented threshing machines, reducing even our dear friends from Ipswich to a bunch of whimpering blue babies.

It’s time the Canaries opened up a can of Norfolk Whoop Ass on the Premier League.

On the Ball City!

Let’s get to work!

Yours,  Jeremy C. Smith. 

TV Link to our nerve agent prophylaxis development work

http://www.wate.com/story/23457797/ornl-researchers-work-to-protect-people-from-deadly-chemical-gases

The Solution to Syria

Amidst the confused public debate as to what to do about chemical weapons and what is happening in Syria, there seems to be no clear consensus as to how best to deter their use.  But the fact is that there was a solution to this problem that, with a bit of thought and development, could have been implemented by now. And it does not involve arming Al Quaeda,  potentially ineffective or counterproductive military strikes or, indeed,  any military strikes at all, and it would not have needed any international agreement.

The solution, which is still the way to go, is to render  chemical weapons ineffective.

Enzymes exist that can act as "bioscavangers", chemically transforming nerve gases such as sarin and VX into harmless molecules by breaking them apart, before they have had a chance to act on the nervous system. But these enzymes need to be improved, developed and translated into field use.

Troy Wymore, Jerry Parks, Larry Avens  and myself  have received a small amount of grant money over the last year or so from NNSA and DOE to work on this using calculations of reaction mechanisms and enzyme engineering. Together with Paul Langan and colleagues we wish to combine these calculations with neutron crystallography to rationally improve these enzymes. We have submitted a paper detailing our first findings, which were quite surprising and exciting and could lead the research in a somewhat different direction. Soon, if, and only if, nerve gas bioscavenging research is properly funded over a long enough period, there will be a primary prophylaxis that military and civilians will be able to use in the form of an injection, patch or pill that will neutralize sarin and other nerve gases before they get a chance to work. This would render any chemical weapons strike useless, which is about as good a deterrent as one could imagine.

However, we, and others in the field,  have had a hard time getting sustained funding for this. It's not that the idea of sarin bioscavanging enzymes is particularly controversial - just that, as usual, the will has not been there to divert money from other, less effective programs to fund development of this technology. $150M over 5 years would probably solve the problem. Financially this makes so much sense, compared to the cost and uncertainty of missile strikes.

And, had this research been funded sufficiently earlier, all those children could have been saved.