Reciprocal Space

A discussion initiated by Katherine Haxton prompted me to check out ResearchBlogging.org and there I discovered the Virology Blog written by Vincent Racaniello. Vincent is a poliovirus researcher at Columbia University; I’d met him a few times while working on the same virus in Boston and it was nice to get back in touch.

Racaniello definitely qualifies as a senior blogger, being a Professor of Microbiology and a very eminent virologist. Astonishingly he has been running his virology blog since 2004. He even has a podcast! Shame on me for not noticing sooner.

On my first perusal I came across a fascinating post on letters Vincent had received from Albert Sabin, the pioneering developer of the oral poliovirus vaccine, a breakthrough that has spared hundreds of thousands the paralysing misery of poliomyelitis. Sabin was arguably a very great scientist, but from what I’ve read he could be, um, difficult. He had little regard for Jonas Salk, a “kitchen chemist” according to Sabin, who developed the rival killed polio vaccine. In fact there was little love lost between the two scientists and their spats have become the stuff of legend.

Racaniello corresponded with Sabin in the ’80s and ’90s following his own breakthrough, the generation of an infectious clone of poliovirus. Some of the letters are a bit technical but they do give a real flavour of a great but acerbic man. One from 1991, composed in the 85 year old Sabin’s elegant longhand, gives a typical taste. He begins charmingly, disarmingly:

First of all, many thanks for your kind letter… (the sweet words were good medicine for an old man’s ego)…

But it is soon apparent that the old man’s ego has not been sufficiently assuaged. Quick as a flash he whips out his machete and starts hacking mercilessly:

It seems to me, that based on the statements in your recent publications, you have either read none of my publications having a bearing on the multiple quantitative phenotypic expressions of individual poliovirus particles… or, if you did, you didn’t learn anything from them…

The emphases reflect Sabin’s angry underlining—I can’t help thinking that he’d have made a wonderfully lively, if vitriolic, blogger! He continues to swipe and stab for another four closely scribed pages but—fortunately—Vincent was well able to defend himself. Or at least the wounds seemed to have healed! Check it out for yourself, if you dare.

You choose, but both paths involve outrageous fortune. Me? I can’t figure it out.

Until six months ago I had never heard of Richard Hamming, a masterful mathematician and computer scientist from Bell Labs. I’d heard of Bell Labs all right, a celebrated hot zone of physics and computational research and home to no less than six Nobel laureates. But of Hamming? Nothing.

Then last year Deanne Taylor blogged about the transcript of a talk Hamming had given in 1986, at the grand old age of 71, on the topic of “You and your research.” I read it and thought it presented a fantastic—if somewhat intimidating—insight into how to do great research. Some of the points made are fairly self-evident, but there are also acute observations and the cumulative effect is quite powerful. Heather returned thoughtfully to Hamming’s article just last week, coincidentally more or less at the same time as I was discussing it in group meeting. So this is well-trodden ground. But at least that means I should be able to find my way.

Or so I thought. I was going to write a detailed and considered piece on Hamming’s talk but it quickly got out of hand; the transcript such a rich repast that I realise I haven’t yet digested it all properly and simply don’t have the time to do the piece real justice. I can flag up some of my own highlights but strongly recommend people to check out the article for themselves. A brutally condensed version was published by PLoS Computational Biology as part of their Ten Simple Rules series.

Bottom line: if you want to be great, brains are not enough. You’ll need total and utter dedication to your work, at the cost of sacrificing other parts of your life. Chew on that, family guys. While you’re masticating there are two other aspects to the hard work business worth mentioning. Firstly—echoing Poincaré—Hamming believes that concentrated study is necessary to feed the sub-conscious mind so that it is primed to worry away at your problem, even when you’re not thinking about it. What dreams may come? Who hasn’t had a great idea or flicker of insight while doing the dishes after a period of intense focus? Secondly, and this is something I hadn’t fully appreciated before (not that great, you see), he makes the telling point that the combination of knowledge accumulation and effort over a period of years work together like ‘compound interest’ to improve your productivity. A similar point about effort and productivity—or achievement—was recently touched upon in Malcolm Gladwell’s interesting thesis that great work (in any field) demands at least 10,000 hours of dedication. Alas, I haven’t been counting.

But there’s more. Hamming recommends you take time out from your every-day regime of hard work to think “great thoughts”, to step back, look at the wider context of your research to see what are its most important facets. About 10% ought to do it; Hamming himself devoted Friday afternoons to great thinking. OK that’s not so original but how many of us make the time to do it?

However, it’s not sufficient just to be thinking in isolation; you need to find challenging conversants with whom you can chew over the fat and gristle of your theories. This last point resonated with my reading of Horace Judson’s superb history of molecular biology (_The Eighth Day of Creation_) in which I was struck by the fact that so many of the major advances came from remarkable pairings of scientists (Luria and Delbrück, Watson and Crick, Crick and Brenner, Monod and Jacob), all of whom would devote large amounts of time to just talking to each other about their work.

And there’s yet more. Heather already mentioned his point about needing courage and confidence to do great work. The confidence needs to be nurtured (sometimes by supportive supervision) and earned, by having the courage to have a go and hopefully reaping the boost to your self-belief that derives from even a small success. On this theme, Hamming made an interesting observation about the post-WWII generation in the Q&A session following the talk. Drawing on his own experience of the Manhattan Project, he felt that scientists who had worked on problems as part of the war effort had derived a great deal of courage and self-confidence by having faced down the adversity of wartime. Because they had had to tackle the problems caused by the extreme duress of war—as much through fear as through courage perhaps—and ultimately been successful, they were poised to just keep on working in the same mindset once the war was over. That particular type of duress is not accessible to us (fortunately) so we are forced to find other means to build our courage and confidence.

Hamming is blunt in his assessments and makes no bones of the fact that greatness comes at a cost. The question is, do you want it? And if so, do you want it for the right reasons? And are you prepared to make the necessary sacrifices? I was glad to see him make the point that the real value of seeking to do great science is in the struggle, not in any transient fame dividend that might accrue from your success. This accords with my own thinking, influenced in part by Pirsig’s Zen and the Art of Motorcycle Maintenance, a protracted argument that the experience of quality is one of profound importance to human beings.

I am not a great scientist. Nor am I likely to be. But I want to be a good scientist, who does excellent work. Hamming’s advice is certainly valuable in this regard and may help me to work more effectively (though I think I can guess what he would have said about blogging…), but there is this endless tension between work and all the other parts of life (shared by many others). The slings and arrows of that balancing act are painful. Even Hamming owned up to suffering from stress for much of his time at Bell labs. I suspect there are many who are better at achieving a healthy equilibrium but I find science a beautiful and terrible lover.

I don’t know what it is about 2009, but I don’t seem to have got going. My posts so far this year have amounted to a note about what’s on telly and a photo of some over-sized dice. And it’s not just in the blogosphere that things seem to be stalled. As ever at work there are many balls to be juggled in the air at once. But I just seem to be juggling without end: I haven’t been able to set even one of the balls down to enjoy a fleeting moment of respite.

My uneasiness intensified this afternoon as I tried to settle to the task of banging out the first draft of a review article that is due soon. Somehow the words wouldn’t come. I guess I haven’t quite figured out my angle for the introduction and need to muse some more. But I wanted to get it done – get it over with.

So I returned home churned with frustration. I’d like to say that I got inspired on the train and am now basking in the glow of having bashed out 2000 words. I’m not because I haven’t. But nevertheless a temporary kind of peace has settled.

I brought home my computer mouse from work for repair. It’s an Apple Mighty Mouse which, like much of that company’s output, is delightful to hold and behold. But it suffers from a design flaw, which is that the little scroll ball gets clogged with gunk and stops working. For the past week or so I could scroll down documents or web-pages but was unable to reverse direction and wind my way back to the top.

This is a common problem and the fix is quite tricky. You have to dismantle the mouse and clean out the grease and dead skin from the scroll ball mechanism. Fortunately there is no end of helpful guidance on how to do this from the worldwide community connected to my computer.

The inner organs of a mouse – cleaned

So I spent a concentrated but pleasant half-hour working at the task. I prized off the plastic ring around the base with a pen-knife, carefully disconnected the wires between the ball and the circuit board and unscrewed the scroll ball housing. The housing, ball and four tiny rollers then had to be swabbed with alcohol to wash away the dirt—of which there was a shameful amount—and the parts carefully reassembled.

The focus on a finicky, practical task absorbed me completely and bestowed a pleasing calm. Happily it was not broken by the sudden pinging away of some miniscule part from my clumsy fingers. They say a change is as good as a rest. There could be something in that! Who knows if the words will come tomorrow but at least I’ll be able to scroll up and down the empty page with some satisfaction!

Sparked by a remark made by Kristi Vogel on blogging with images, here is one that’s been hovering at the back of my photo collection.

Does God play dice?

Apparently, despite Einstein’s objections, the deity is a bit of a gambler. What is disturbing is that this picture was taken in Palermo, Sicily last summer so it seems He may have been gambling with the mafia. ‘The discovery of the enormous dice at the water’s edge surrounded by concrete blocks was a possible indicator of foul play,’ said police.

This is normally Matt’s brief but I thought people (in the UK at least) might be interested to know that a three-part series on Science and Islam, fronted by Prof Jim Al-Khalili, starts at 9 pm tonight on BBC4.

The first part is all about Al, or al-Hassan Ibn al-Haytham to give him his full name, an Islamic scientist born in 965 AD whom Al-Khalili describes as the ‘first true scientist’.

Al-Khalili’s earlier documentary, Atom, on the birth of modern physics was very watchable, so tonight’s offering should be good.

It’s easy if you try. I’ve never much cared for John Lennon’s song: despite the wistful melody and admirable sentiment, the scientific precisionist in me could never quite get past the poor grammar. “And no religion too, Mr Lennon? And no religion either!”

But the song does at least draw attention to a very important human attribute: imagination. And, if I might swivel alarmingly to another, distant point on the pop cultural spectrum, the value of imagination has also been heartily endorsed by Spongebob Squarepants. In Idiot Box, one of the show’s best ever episodes, Spongebob and his starfish pal Patrick are awaiting delivery of a new television. When it arrives their sour-faced neighbour Squidward is aghast to see them toss away the TV so that they can play with the huge cardboard box that it came in, using just their imaginations! Squidward purloins the TV but is driven to distraction because he simply cannot fathom how Spongebob and Patrick can have so much fun with their box-imagination combo.

Most parents will recognise in this the small child’s delight with the fantastic play value of a large cardboard box. But many of us, caught up—like Squidward—in our preoccupation with the daily grind, may have lost something of that capacity for imaginative leaps.

I was struck by this thought a few days ago when watching a film about another imaginative leap, Neil Armstrong’s famous “giant leap for mankind”. This was recalled in a brilliant and thoughtful documentary about the Apollo moon landings, In the Shadow of the Moon, which was broadcast in the UK by Film4 (yes, I was watching TV!). The film’s makers scored a double coup in their production for not only did they dig out some very rarely seen footage of the Apollo program, but they also conducted lengthy and thoroughly researched interviews with ten of the surviving astronauts. Although Armstrong himself—apparently a bit of a recluse—did not participate, the other astronauts reflect candidly, often with wit and intelligence, on their remarkable experiences. It’s a wonderful piece of work.

The film appealed enormously to the star-struck child in me; I saw it as soon as it came out in the cinema late last year. Many years previously, as a twelve year old responding to a competition run by the Belfast Telegraph I’d won the chance to visit the Armagh Planetarium to put a question to Jim Irwin, an astronaut who had landed on the moon as part of Apollo 15 in 1971. Concerned for the poor soul who was left behind in the command module and never made it to the moon’s surface, I asked him how they decided which member of the crew should miss out. The answer—that this was simply decided early in the training program—was rather banal but the event nonetheless shines in my memory, touched by lunar magic. When I saw In the Shadow of the Moon again recently I recalled some of that magic. But I was also even more impressed than on my first viewing by the drama of the story and the humanity of the astronauts. The short trailer on the film’s website gives a good idea of the content.

One of the most interesting aspects of the Apollo program, as pointed out recently in The Guardian, is that in setting out to explore the moon the astronauts also made entirely unexpected discoveries about the Earth. The moon missions were the first to thrust men so far into space that they could see the planet in its entirety. One of the most resonant photographs taken by the astronauts of Apollo 8, the first to reach lunar orbit (on Christmas Eve 1968), was of the Earth rising slowly above the lunar horizon. I guess everyone has now seen the famous ‘Earthrise’ image of the blue-white globe ascending over the dusty, lifeless surface of the moon.

Earthrise – spot the difference

Continue reading →

Yesterday morning I awoke in crumpled clothes on a strange sofa, my mouth feeling furry and unwashed. I’d crashed there at about 5.30 am and only snatched a couple of hours of fitful sleep. As I gazed blearily at unfamiliar surroundings, a woman I barely recognised appeared and asked if I’d like a cup of tea. I nodded and mumbled thanks.

Partying hard in the run-up to Christmas? No, it was the aftermath of another synchrotron trip, this time to the Diamond Light Source just outside Didcot.

The symptoms will be familiar to most protein crystallographers: puffy eyes, grey complexion, mental derailment, churned up guts that are no longer in sync with mealtimes. Jet-lag without ever having left the ground.

Three of us had arrived bright-eyed on Wednesday morning for our first data collection trip on the micro-focus beam-line (I24) at Diamond. The beam-line is a work in progress since the experimental station isn’t quite fully operational. But it works well enough to be useable and in a mutual back-scratching agreement with Gwyndaf, the beam-line scientist, we’d managed to snag some time for our project. I24 focuses the intense X-rays generated by the accelerator ring into a beam that is only about a tenth of the thickness of a human hair—around 10 µm—just what we needed since our crystals were tiny needles of about the same size.

The crystal (invisible!) is on the end of the horizontal pin in the centre of the photo

It’s amazing that such miniscule crystals can be used to scatter X-rays into the diffraction patterns needed to figure out the structure of the molecules within. But tiny crystals make for tricky experiments. So we fiddled for hours, scooping up each one and freezing it in a stream of nitrogen cooled to 100K. The frozen crystal—trapped in a gobbet of cryo-solvent—is imaged by a microscope so that we can manoeuvre it precisely into the path of the beam. But seeing a tiny crystalline shard embedded in a glistening bead that bends and reflects the light is no easy feat.

Even then the X-rays are so intense and the crystals so small that ten short exposures were enough to frazzle the protein. So you stop and shift the crystal needle along to blast a new section for another 10 exposures.

And so the night passed, myself, Olga and Jingjie locked in intense rounds of sample preparation and analysis, of activity and concentration. We were cheered when rows of dark spots appeared on the detector, dismayed when there were none. Midnight came and went and the wee small hours were upon us. It’s strange, but you can keep going as long as you’re active, as long has you have a purpose.

But we finished around 5 am, tidied up and crashed. And when you do stop your body finally catches on to the punishment you’ve been giving it and strikes back with a vengeance. We slunk back dead-beat from Diamond.

The name was well chosen: diamonds are bright but they’re also hard. Well hard.

Here is the second of two guest blogs from my tutorial students, completing my inverted blogging challenge. This one is from Louie Barnett, who provides an entertainingly seasonal take on the murky world of G-protein coupled receptors. Take it away, Louie:

Continue reading →

I know, I know—the challenge is supposed to be about getting more senior people into blogging but I turned it on its end and set a mini-challenge of my own to my new batch of Biochemistry undergraduate tutees. I asked them to write no more that 400 words on any topic from the course that had particularly grabbed them. Provoked by the conference session on blogging in education, I tried to tap in to the zeitgeist, and told them to write their piece in the style of a blog.

And I was astounded by some of the responses that I got. Two in particular I thought were worthy of wider dissemination so I asked the students if they’d like to guest on my blog. Happily both agreed so here below ladies and gents, for you delectation, amusement and education, is the first from Yvonne Liu, who wrote about the lectures I gave on thermodynamics…

The second will appear early next week. I encouraged both students to sign up to the network so they may be brave enough to respond to any comments!

Continue reading →

Gazing at the very first model of a protein structure determined by X-ray crystallography Max Perutz, one of the founding fathers of the technique, was disappointed. It may have gone unspoken at the time but the initial coiled, worm-shaped creation resembled nothing so much as a giant turd. “Could the search for ultimate truth really have revealed so hideous and visceral-looking an object?” lamented Perutz.

Polished, but still ugly? (From London’s Science Museum)

But that early dismay was soon forgotten. The first model of myoglobin, an oxygen-storage molecule from the muscles of sperm whales, was based on relatively low resolution data and revealed only the overall fold of the protein polypeptide. As crystallographers worked their crystals, getting them to scatter X-rays at higher and higher angles, the atomic details of the molecular structure were soon revealed. The consternation at the irregularity, the lack of symmetry in proteins—where was the slender elegance to mirror DNA’s double helix?—soon evaporated before the glittering galaxy of atoms and bonds.

Which brings me to a wet weekend in Hamburg. Last weekend in fact when I found myself at the synchrotron, along with two members of my group, peering into a microscope at three O’Clock in the morning and trying to fish out tiny protein crystals with a miniscule loop of nylon attached to the end of a metal pin. Well, they weren’t that miniscule by modern standards; in fact the crystals were rather chunky—about 0.3 mm on each side.

Once caught, the crystal was placed in the direct line of fire of an intense X-ray beam. We retreated from the lead-lined experimental hutch and instructed the computer to open the shutter.

And when we did so, our mouths dropped open too: the crystal diffracted to 1.4 Å! In the lab it had only gone to 2.7. We were hoping to do better than that at the synchrotron but 1.4 took our expectations and booted them out of the stadium. What can I say? We were very pleased!

And why exactly? What do these numbers mean? It tells you how much detail you can expect to see in your electron density maps, the three-dimensional chicken-wire that we compute from the data to reveal the shape of our molecule.

Look!

And I have just this afternoon gazed upon the electron density map. And now you can see it too. It still looks like worms but this time they are knurled and knobbly; you can just about see that the molecule is constructed of tiny spheres. Atoms. In places, even the hydrogen atoms, each with just a single electron, can be seen protruding shyly from the density. In all my time as a crystallographer I have never seen a molecule in such glorious detail, and neither has anyone else in the lab. So today everyone is wandering around with smiles on their faces. And nobody is mentioning poo.

Continue reading →

Blogging is mainly writing and writing—according to one informed source—is like having a poo.

I have just seen the excellent Screenwipe, hosted by Charlie Brooker on BBC Four (that’s the TV, not the radio). It doesn’t appear to be on their iPlayer, I’m afraid*. There’s a re-run on at 00:50 but that’s in less than an hour’s time, so you’ll have to be quick!

Brooker usually offers a caustic and often hilarious analysis of TV (for a taste, see this Guardian piece on Dawkins’ program – that’s the science link taken care of) but this evening’s offering was instead an amalgam of interviews with various successful TV writers including Russell T Davies (Dr Who), Graham Linehan (Father Ted, The IT Crowd), Paul Abbott (Shameless, State of Play) and others. What I really enjoyed was that they were all given time to speak and Brooker had clearly asked some good questions.

I was impressed by the tremendous effort that all acknowledged was devoted to the multiple re-writes needed to shape the final piece. Gives us all hope.

But what struck me most was the incredible degree of procrastination that all the writers interviewed admitted to. Linehan made the point that this was necessary to feed the imagination or the sub-conscious, a necessary pre-amble to any good script. And he went on to compare writing to havng a poo: “It’s really hard to go if you don’t need to, but sometimes you can’t stop yourself!”

**Update:* The show is now available on iPlayer (for the next 7 days) for those with access (UK residents?). Well worth a look – there’s much more to it than the crack about pooing…!

I’ve rolled my rock to the top of the mountain and sat down for a rest. Tonight I will allow myself a brief respite from my labours. I’ve been working very hard of late but the job is now done and I feel a great sense of relief.

Having been made a professor about a year ago, on Wednesday night I finally got around to delivering my inaugural lecture to an audience of family, friends and colleagues. This was my chance to explain myself – to give some account of what I’ve done in my career in science, and perhaps some suggestion of what is to come.

I have never in my life sweated so much over a lecture. The breadth of the audience made it very difficult to judge how to pitch the content so that as many people as possible could follow what I had to say. There is no set format to these things, but that freedom seemed only to magnify the problem of preparing the talk.

The lecture had been on my mind, with slowly increasing intensity, for the past several months. A few weeks ago I finally started shaping my scattered notes and making slides. I had a reasonably finished draft come last weekend but didn’t get around to having a run-through until Tuesday—at about 11.30 pm. I was a bit shocked to discover that it was way too long—1 hour and 13 minutes—and rather disjointed. I spent the next few hours trying to trim the fat, but when I hit the sack at 3.20 am, it was still not right.

I was in my office early on Wednesday morning, my guts in knots, and spent most of the day trying to streamline the presentation and re-work the connections between some slides. It was all a bit intense but I did manage to have a couple more run-throughs and things were finally taking a shape that seemed to be hanging together. I managed to smile and chat to a few people who arrived to have tea before the lecture. The sight of so many friendly faces appeased my nerves. But only slightly.

As I rose to speak, and fiddled with the clip on the microphone—sending out loud booms and scrapes into the theatre—I knew that if I made a decent start, things would probably be OK.

I managed not to fluff my lines for the first few slides and settled to the task. And then started to enjoy myself. Beginning with my recollection of a unusual announcement heard on the platform at Tooting Bec tube station—‘If your destiny is not shown on the board, please take the first train and change at Kennington’—I tried to describe the path that had taken me from a childhood in Northern Ireland to a professorship in structural biology at Imperial College. Much of it seemed to be something of a random walk but the journey, though extremely arduous (positively Sisyphean!) at times, was never less than interesting.

I’m too tired to rehearse the content here in any detail tonight (though some of it may well be re-cycled for use in future posts!). But the weight of the task has finally slipped from my shoulders—I have been released from my bond. And tired though I am, I also I feel strangely re-energised for the work that lies ahead.

Let’s roll that rock some more!