I get my kicks from thermodynamicks!

In the past couple of weeks I have been trying to convey to my students something of the glory of thermodynamics. It’s not an easy or popular subject, especially given the mathematical content. But I do love it so!

I know it seems dry: heat, work, entropy, state functions, the second law. The zeroth law for God’s sake. But peel away the yellowing, crackling paper and underneath you will find a vibrant subject that is alive with science and history. What it shows is that concepts we now take almost completely for granted, like work and energy, were actually hard won. I have been telling my students about the origins of the concept of heat and therein hangs quite a tale.

No less a figure than Lavoisier listed heat alongside hydrogen, oxygen and nitrogen in the table of elements from his famous Elements of Chemistry textbook, published in 1789. At that time heat was thought of as a substance, a fluid—igneous fluid or caloric—that pre-existed within matter and could be released in chemical reactions.

But Lavoisier was guillotined five years later during the reign of terror that followed the French revolution and soon after the idea of caloric was also knocked on the head. This latter revolution was not the work of a brutal, faceless committee but due to Benjamin Thompson, an infuriatingly delightful character, also known as Count von Rumford.

American by birth, Rumford sided with the British at the outbreak of the revolutionary war and eventually fled to London. There he proceeded to upset the British authorities and soon found himself working for the Prince-elector of Bavaria, in charge of munitions. In this capacity he could observe closely the manufacture of cannons—which were cast in solid brass and bored out to create the barrel—and “was struck with the very considerable degree of heat which a brass gun acquires, in a short time, in being bored”. These observations stimulated an ingenious series of experiments, which he published in 1798 as a paper entitled “An Inquiry concerning the Source of the Heat which is excited by friction”. Thanks to the good offices of JSTOR you may be able to download the paper as a pdf and it’s a cracking read.

In the manner of the time, Rumford’s article is written rather discursively. Here and there he reflects on how he feels about his experiments and achievements. It’s an insightful style that brings plenty of colour to the usual verbiage of scientific reporting—one that we might do well to re-discover.

From the start it is clear that Rumford is not a man wracked by self-doubt. Addressing the learned fellows of the Royal Society, he advances the view that an ordinary working life affords plenty of opportunities for scientific contemplation and goes so far as to claim that, for him, the happy circumstance of his occupation has more often led to “useful doubts, and sensible schemes for investigation and improvement, than all the more intense meditations of philosophers, in the hours expressly set apart for study.” Way to get an audience on your side.

Switching tack, he tries a little modesty. And fails. Rumford temporarily concedes that his experiments may not warrant such a grand introduction but then avers, “I cannot help flattering myself that that they will be thought curious in several respects, and worthy of the honour of being made known to the Royal Society.”

Rumford's cannon
Rumford’s cannon – plug and borer on the left. Water-filled box not shown.

Rumford details his experimental set-up, which uses a cannon cast from solid brass. The Bavarian cannons were cast vertically, muzzle up, as a solid piece about a third longer than the finished product; the additional weight from the extension served to compress the metal that would form the muzzle of the gun, bolstering its strength. Rumford put this extension to the service of science. He worked it into a hefty plug connected to the main barrel by a short neck and then hollowed it out to accommodate the borer, blunted to increase friction while reducing the rate of erosion of the brass. In this way, the borer and plug could be encased in a watertight wooden box.

Then comes the boring bit. By which I mean, of course, the really exciting bit.

Continue reading

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Bluetiful!

Quick! Look! This is a coucil flat in Southark but it’s cool and blue and rather beautiful.

There was a brief report about it last night on Channel 4 News, which you can watch here. They explain how the artist Roger Hiorns created the work by flooding a derelict, sealed flat with hot, saturated copper sulphate solution.

Seizure
Seizure by Roger Hiorns.

The whole of the interior is coated in deep blue crystals.

This I’d like to see up close and, apparently, you can.

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Music that’s bound to be interesting

The inestimable Dr Rohn has, on more than one occasion, sung the praises of the engineering prowess of her lab-mates. But in this week’s Nature music and ingenuity were combined to produce a new high note of technical wonderment. A fascinating News and Views piece directed my attention to a recent paper* by Hua-Zhong Yu and colleagues at Simon Fraser University in Canada.

The Yu group have created a ‘home-made’ micro-array on a music CD that just needs an ordinary CD player to scan the disk for the results of the binding assay.

They did what!?!

You heard right – and their system is impressively flexible since interactions involving DNA and protein can both be analysed. First, the CD is treated so that spots at defined positions on the surface will allow covalent attachment of DNA or proteins. Biotinylated DNA or protein samples are then added to perform the binding assay and in the final step the bound material captures strepavidin-labeled gold nanoparticles. A simple chemical treatment deposits silver on these gold seeds, so the tiny spots containing bound DNA or protein end up coated with silver clusters.

Then comes the devilishly clever bit.

The disk can be inserted into a standard CD player to analyse the results! Because music CDs have been designed to play back smoothly even when they get scratched or dirty, the music is encoded in a way that allows error detection and correction. The software analyzing the readout from the disk knows precisely where the errors on the disk lie. Now, normally you don’t care about the errors; you’re only interested in hearing a faithful rendition the toe-tapping tunes of your favourite combo (‘Hold on Tight’ by The Electric Light Orchestra anyone?), but with freely-available software tools, you can access the error information and that is exactly what the Yu group have done.

Since the silver clusters scatter the laser light just like a defect, each spot of bound proteins can be found on the treated disk. And not only that: the software also reports the size of the defect, which in this case is proportional to the amount of material bound, so the interaction can be analysed quantitatively. Yu and co showed they could measure DNA hybridisation, detect SNPs and determine antibody-antigen affinities.

How cool is that? As Ian Dury put it, “There ain’t half been some clever bastards!”

*Yunchao Li, Lily M. L. Ou, Hua-Zhong Yu (2008). Digitized Molecular Diagnostics: Reading Disk-Based Bioassays with Standard Computer Drives Analytical Chemistry, 80 (21), 8216-8223 DOI: 10.1021/ac8012434

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About a blog

Taking my cue from Martin’s excellent suggestion, and following Henry, Steffi, Eva and Maxine, here’s my tuppence-worth:

1. What is your blog about?
Usually about 500 words… on the subject of the underbelly of science. The guts and bolts, so-to-speak.

2. What will you never write about?
Real-time experimental results – my lab-books are closed until peer review. Sorry Cameron.

3. Have you ever considered leaving science?
Yes.

4. What would you do instead?
There was a time at the end of my PhD when I thought I wanted to be a hospital manager and joined the NHS for 10 months. It was not a marriage made in heaven. Lately I’ve been thinking of applying for jobs in Hollywood…

5. What do you think will science blogging be like in 5 years?
No idea. No, really – not a clue.

6. What is the most extraordinary thing that happened to you because of blogging?
Well, it’s a bit early to say since I’ve only been in this game for a couple of months. I have certainly enjoyed getting to know people, some of whom I’ve even met in first life! And it’s great to have an outlet for writing about science that some people actually seem to read. And while I enjoy the scientific community round here, I would like to see NN expanding its audience outwardly.

Oh, and my kids think I’m a little bit ‘cool’ to be blogging!

7. Did you write a blog post or comment you later regretted?
Not apart from this one.

8. When did you first learn about science blogging?
Relatively recently – probably within the last 2 or 3 years.

9. What do your colleagues at work say about your blogging?
I’m still waiting for most of them to find out. I haven’t advertised it widely where I work and no-one who knows about it has yet passed comment.

10. Extra credit: are you able to write an entry to your blog that takes the form of a poem about your research?
Well, I think I started that – surely my credit’s good? In any case, my muse is all wrung out this week!

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Public Engagement Ring

Cath Ennis wrote back in June about the reluctance of some of her colleagues to write lay summaries of their work when applying for grants. Clearly for some scientists the effort of casting their work into a form that is accessible to the general public is just too much like hard work.

But, as has often been stated on NN, making our science intelligible to the public is a valuable activity. Indeed many would say it is necessary. And while I can certainly understand that some of us might prefer not to spend time on this at the end of the laborious process of assembling a grant application, that’s not much of an excuse.

So I wondered if there might be a way to make the process and the result more engaging and for my last grant application – an investigation of the peptide cleavage specificity of an important viral protease – I wrote the lay summary as a short story. In fact it was an extremely short story since there was a limit of 200 words. You can peruse the result at LabLit.

One of the main difficulties is finding ways of avoiding jargon but still getting the essence of the science across – all while staying within the word limit. I suspect I haven’t been wholly successful in this instance but practice makes perfect (!) and at least the composition was much more enjoyable than usual.

I humbly propose this as a new (and exciting?) way of writing lay summaries to really catch the public’s attention. Care to join the ring? For my next grant application, I am considering a more poetic form…

Shall I compare thee to a summers day?
No! A nonsensical hypothesis!
Your DNA sequence will show the way
And give a much truer diagnosis…

Then again, maybe not.

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“Donuts – is there anything they can’t do?”

On Tuesday, following a tip-off from Maxine, Richard noted the passing of the Daresbury Synchrotron in Cheshire, which shut down finally in August. This gave me pause for quiet reflection since I had been a Daresbury user since 1991, cutting my teeth as a crystallographer by spending long nights in the darkroom developing the film packs that we used to record the X-rays scattered by our crystals.

More often than not we would come away pretty satisfied with the outcome of those long hard nights. Sometimes we had more than 48 hours of beam-time to sweat through and would struggle home with a kind of jet-lag having worked odd hours of the night and day. I remember on one trip (when I was running a group of one – yours truly) working a 48 hr stretch entirely on my own. By that time they had at least made the switch to electronic detectors which you could leave running on automatic for the hours needed to collect the data – so I could get some snatches of sleep.

However, these days the introduction of CCD detectors means that you can grab your data in as little as 30 minutes, so the turnaround time between crystals is much faster and there is little time for a break. That’s assuming that your crystal diffracts X-rays in a nice orderly fashion – more often than not, instead of orderly ranks of spots, you see a few irregular black smudges – and that means only one thing: next crystal please!

So trips to Daresbury were never easy or relaxing – there was plenty that could go wrong, not just with our crystals but also with the machine, which every so often would decide unceremoniously to dump its current of electrons, turning off the X-rays that were probing the innards of our proteins. But along the way we still got plenty of useful data to kickstart quite a few structural projects. We even have a few structures determined using Daresbury data that are still to be published (manuscripts in tardy preparation) – as, I imagine do other groups – so we haven’t yet heard the last of the Daresbury synchrotron.

Yet as Daresbury flickers and fades a new X-ray source has ignited in the middle of the Oxfordshire countryside. The Diamond Light Source is now open for business and, co-incidentally, I was there yesterday helping to chaperone a group of UG and PG students from Imperial who were visiting for the day to discover what a real synchrotron looks and feels like.

Diamond Synchrotron, Didcot, UK
Diamond – the donut has landed

Diamond is a truly impressive facility – a massive, gleaming donut of a building. It reminded me of my favorite quotation from Homer Simpson which I have pinched for the title of this piece. It is also the workplace of NN blogger Sara Fletcher with whom I was delighted to catch up yesterday and who will no doubt tell us more about life at Diamond in blogs to come.

The curved experimental hall contains a huge concrete tunnel that houses the accelerator or ‘storage ring’. The ring is basically an evacuated pipe, a few cm in diameter that is surrounded by radiofrequency cavities to keep the electrons whizzing round at close to light speed and magnets to steer them through the ring. Every so often a magnetic insertion device causes the electrons to shimmy as they pass. This electronic wiggle releases a burst of intense X-rays down the beam-line and into the sample – which in our case is a tiny crystal of proteins, often no more that 0.1 mm in size. The beam-lines fan out tangentially from the ring – at present there are about 20 of them.

Diamond - electron storage ring
The storage ring – tasty!

But I’m getting way too techie. While I wipe the flecks of foam from my mouth it will suffice to say that with Diamond the good work of X-ray analysis initiated at Daresbury will continue. The torch has passed and fortunately is brighter than ever!

Oh, and one more thing. I was pleased to see that the section of the storage ring that we visited was housed in “Zone 13”:

Zone 13 at Diamond
A logically named zone

Last week I spent several nights in a hotel that had no room 1013 on the 10th floor, presumably as a sop to the superstitious. It is good to report that no such nonsense is tolerated at Diamond!

Posted in Protein Crystallography, Scientific Life | 23 Comments

The battle for my eternal soul

Let’s face it: scientists aren’t in it for the money (except perhaps those with a more entrepreneurial bent). More often we are preening our egos and chasing a kind of immortality—the chance to create a legacy that will outlive us. Of course, this is an entirely irrational goal, coming oddly from a profession that often spouts its single-minded adherence to rationality!

But I guess many of us also hope that our work will improve our understanding of the world and perhaps enhance the quality of life for humankind, by producing treatments for disease or other kinds of technological advances. That at least is a more rational ambition.

In my work as a protein crystallographer I often find myself on the periphery of the most current mechanistic investigations because the long lead times needed to generate structural information by this technique make it difficult to produce results synchronously with the latest functional studies in the field. I had this sensation recently at a meeting in Sicily on foot-and-mouth disease where our work on the structure of one of the viral proteases was received with some interest but did not impact the major concern of most attendees, namely vaccine efficacy.

HSA crystals, à la Warhol
HSA crystals, à la Warhol

However, here in Japan I am attending a symposium* that is devoted to the function and properties of just one protein, human serum albumin (HSA), and I find myself in the happy position of leading a group that in the past 10 years has solved the structures of over 40 complexes of HSA with different small molecule ligands. This places us at the forefront of structural analysis in the albumin field and it is very gratifying to know that our results are widely read and have had a great impact on the work of many different laboratories around the world who also study this abundant and remarkable protein.

The structure helps us to understand many different aspects of the protein — its role in transporting fatty acids, in perturbing the pharmacokinetics of drugs, and how genetic variations may be associated with hereditary conditions — and to think about ways to exploit it’s transport properties in the development of novel therapeutics.

So, this time I find myself not at the periphery but in the very centre of things. I was invited to present the first talk of the day and have had many generous and stimulating comments from my international colleagues. I am extremely gratified that our work has been received so well – it is balm for my restless spirit. Such are the delicious but transient pleasures of scientific inquiry.

I hope you will forgive me for ‘bigging’ myself up in this outrageous manner. Please be assured that tomorrow my soul will return to the tortured hell of corrosive self-doubt.

*Symposium – the modern meaning is ‘conference’ but I prefer the original Greek definition: drinking party!

Posted in Protein Crystallography, Science | 12 Comments

Blog power in the service of science?

Taking my cue from Ben Goldacre’s comments at SciBlog08, I’d like to unleash the power of the blogosphere. I want to see if Nature Networkers can shed any light on the interview that I heard early this morning on the BBC Radio 4 Today program (listen to the 4 min item at 7.21 am).

Prof Ford, a writer and broadcaster (and visiting professor in e-learning at Leicester University), converted the electrical signal from a nerve cell into an audible sound and claimed that this revealed a kind of cellular intelligence. As far as I can tell, this ‘finding’ is not based on any kind of peer-reviewed research. It seemed to be pure supposition on the part of Prof Ford.

But my expertise is not is this area. Can anyone out there dig up any support for Prof Ford’s interpretation (I found nothing on Pubmed)? Or am I correct in thinking that this is non-science (aka nonsense)?

(Incidentally, this interview linked in to an interesting discussion on scientific authority—’Hierarchy in Science’—over at LabLit).

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It was the blog wot won it!

My co-stars and I are €400 richer thanks to this blog becasue I am delighted to report that our recent video was awarded first prize in the competition run by the organisers of the EuFMD Meeting on the Global Control of FMD, Tools, Ideas and Ideals (held just this past week in beautiful Sicily).

Musee del Sale, Salines, Sicily
Sunset in Sicily last Wednesday

The award was based simply on the number of hits that each entry received and our effort—shamelessly pimped on this site—was far and away the most viewed. So thanks to everyone who gave their support!

Blog power – you can’t beat it!

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Out of the lab and into the world

Most days you can call me Mr Molecule for I am to be found with my head buried in a thicket of atomic bonds. But every so often I pull myself free of my protein structures and take a look at the world outside.

That’s what I’m doing today because I have come to the charming old town of Erice in Sicily to attend an EU conference on the control of foot-and-mouth disease (FMD). Those of you in the UK will be familiar with this viral scourge of cloven-hoofed livestock since there have been outbreaks in recent memory—in 2001 and 2007.

EUFMD-courtyard

But this is not just a local difficulty; it is a worldwide problem. The global nature of the disease was emphasized on the first day of the conference. We had talks from scientists from Brazil, Argentina, India, the USA, Russia, Iran, China, Holland, Germany, South Africa and the UK. And the message is that this disease is far from licked. It is endemic in many parts of the world and will require a truly concerted effort to reduce the level of incidence.

The virus has been known and investigated for over 100 years but there is still much to be learned about the molecular, cellular and immunological aspects of FMDV infection. But tackling this disease will also require plenty of work outside the immediate confines of the laboratory. Many of the regions affected are poor and inaccessible, so it is difficult to maintain effective surveillance of the identity of the most prevalent circulating strains. As with many other viral diseases, vaccine stocks need to be matched to the virus types occurring in the field, but the reliability of measures to determine the efficacy of vaccines against strains that they do not match perfectly is a point of keen contention. In Africa, disease control is difficult because many of the farms are smallholdings, where animals are not restricted by fences and live in contact with wild buffalo that are a natural reservoir for the virus. In India the fight against FMD is complicated by the sacredness of cows – they simply cannot be slaughtered.

And yet we have gathered on a rocky mountain-top in Sicily as a global community seeking to pool our ideas and to plot a way forward. There are tensions and concerns. The mosaic of small-scale studies seems to not quite add up to the sum of its parts. The efficacy of vaccine preparations is a variable feast. And in private someone posed the ‘unspoken’ question: how much does it suit the rich, disease-free nations to have FMD in countries that might otherwise compete for their meat markets?

I am on the periphery here, peddling my structures, so I may be misreading things. But there are detectable currents of cooperation and, although there are clearly difficulties ahead, I am heartened by the sense of the scientific community, at work.

P.S. Internet connection rather patchy here – please don’t be disheartened if I don’t respond promptly to comments!

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A reciprocal space in Nature

I couldn’t not do a quick post about this – today’s Futures story in Nature which provides an interesting medical twist on Oscar Wilde’s The Picture of Dorian Gray, a tale that resonated with me a couple of weeks back. It’s beautifully done – go read!

(I’m afraid, however, that the article may be behind a pay-wall but I hope most of you can access it.)

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The geeks might inherit the earth

“The problem with the French is that they don’t have a word for entrepreneur.” Thus—allegedly—spoke soon-to-be ex-President George Bush. It may be an apocryphal tale but I do so want it to be true.

And speaking of entrepreneurs, Michael Birch, founder of the social networking site bebo.com, gave a talk at Imperial a couple of weeks ago. Birch, a physics graduate back in 1991, was speaking at the College’s Alumni Reunion.

You can stream the video of the talk or download it as a podcast1. Birch is an engaging and fluent speaker and has an interesting tale to tell of his student days, his early employment developing databases for an insurance company and then his various attempts to develop a successful business on the web. The account of his initial efforts is really quite revealing – there were several non-starters before he finally got bebo.com off the ground. This kicked off as a very small business with his wife and brother but eventually grew into the success that is so well known today and that they sold to AOL this year for £850 million. Not too shabby.

It’s a fascinating account—especially for anyone interested in Web 2.0— told in a nicely self-deprecating manner. There are some touching recollections about his father – also a bit of an entrepreneur it would appear. And for those interested in making presentations, there was a very nice innovation: he gave a few keywords to his kids (aged 7 and 9) and got them to draw the slides that were shown in the talk!

1NB: the video is about an hour long, but it’s mostly footage of Birch talking so you could easily listen to it on the go (and check out his kids’ pictures later – there were only about five of them).

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