Mind the Gap

Writing a paper – it takes on a whole new meaning if you’ve spent time behind the editorial desk of a peer-reviewed journal or two. It’s now been about a year and a half since I left publishing to return to the bench, and I’m busy finishing up the experiments for my first research paper. But in the meantime, my boss and I (which of course translates to I, for the most part) were recently asked to write a review article, and I’m just in the final throes of that.

And in taking on this task, I’ve realized that knowledge of what goes on On The Other Side can seriously alleviate publication anxiety. First of all, the London publishing world is extremely small, and its pool of editors, highly mobile. It turns out that the person handling my manuscript is the fellow Assistant Editor I sat next to in my first journals job back in 2003. It is sort of hard to take her formal ‘your article is nearly overdue’ emails seriously when, in the back of my mind I remember the three of us giggling, groaning and rolling our eyes over the various outrageous excuses that some authors would send us for being late. Of course, the knowledge that this editor knows that I know means that I can’t use any of those tactics myself. Back in December when I was seeking a much-needed extension of the deadline, I didn’t even try:

Dear {censored}

I won’t pawn you off with any of the normal lame authorial excuses like the dog having ate my first draft or some sort of illness or death in the family — I simply haven’t had a chance to do much yet, down to my own lack of organization and time management.

Of course the extension was duly granted, with good grace – having been an editor has also taught me that if you want something finished by February, then the preceding December is a pretty good place to draw that first line in the sand. (Oops, I haven’t betrayed any deep-dark editorial code by sharing this with you, have I?)

She’s gone on maternity leave now, and my file has been passed on to someone else. A few days ago I wasn’t sure exactly what tack I should take on a particular issue – so I rang up her replacement, introduced myself and we had a productive chat. Oh, and I got another few days’ grace on the deadline in the process. When I put the phone down, a few of my colleagues were stunned. It turns out that to most scientists, the thought of actually speaking to an editor had never even crossed their minds. Instead, writing a paper seems to be a stylized, us-versus-them battle where the lines of communication are strictly via emails loaded with formalized sentences dripping in ambiguous subtext. An editor, in this environment, is more enemy than ally.

I guess I used to think that too, until I stood in their shoes and realized that producing a great paper is a goal that both authors and editors have in common.

Live in or near London and interested in reading lab lit — novels about science or scientists? It’s never too late to join Fiction Lab, our monthly geeky book club at the Royal Institution.

Last Monday we dispatched our first book of 2009 — This Thing of Darkness by Harry Thompson, a Patrick O’Brien-esque tale of the voyage of the Beagle told primarily from the point of view of its troubled, intelligent gentleman captain, Robert FitzRoy. The book got fairly good marks from our snarling den of hard-to-please hyenas (you know who you are), though weighing in at about 900 pages was not seen as an asset. Nevertheless, our most negative member was as usual not impressed: he thought the book was ‘naval porn’ and should have been retitled This Thing of Dreariness. Also, the prevailing view was that Darwin was made out to be a two-dimensional caricature, as if the author was so interested in showing us the mortal behind the godlike reputation that he over-compensated just a wee bit and made him into a crashing bore.

Nevertheless, most of us agreed that the portrayal of the voyage was vivid and engaging. One lass, bless her, hadn’t read the book and knew nothing about Fiction Lab but showed up on the night solely because she’d been round to see the current exhibition at the Natural History Museum, was baffled at how all those specimens could possibly have fit on such a small ship and wanted to learn more. (The answer? Crates were shipped off at every port of call.)

For the record, though it certainly ended tragically, I liked the book and felt I learned a lot. And I appreciated the occasional touches of humor. My favorite phrase from the book? “The poop deck was cleared of tortoises”.

Because of our late start this year, time is getting short, but you still have time to buy and read next month’s book, The Behaviour of Moths by Poppy Adams – especially as it is only 305 pages in a lovely large font.

The novel, it is said, invites us into the world of two elderly sisters who have not seen each other for decades, reunited in the sinister old family home. Ginny, a recluse who never leaves the house and survives by gradually selling off the family furniture, also happens to be the world’s foremost expert on moths. When her sister Vivi comes to visit, a dark family secret gradually emerges from a network of flashbacks and childhood memories. Why has Vivi chosen to return after 47 years? Can everything that Ginny remembers about their childhood actually be trusted? And what is she trying to hide in the attic?

I’ve only just started, but already have a feeling that this might be one more for the ladies — which is not necessarily a bad thing after 900 page of hoisting the mainsail and hosing down the barnacles. I’m fairly certain it’s going to be what I call ‘lab lit lite’, with the science pretty peripheral to the overall story, but after a few pages, I want to keep reading. The author, a science documentary maker for the BBC and Channel 4, lives in London, but so far her agency has resisted the charms of my various email attempts to invite her along on the night – I’ll keep you posted! In the meantime, buy yourself a copy and join us at 7 PM on 2 February.

Note added in proof: I see that Nature Network still hasn’t fixed the bug that prevents us from posting urls that have ampersands in them, but if you google the RI and then type the name of the novel into the search box, the relevant Fiction Lab page will come up. How deliciously old-fashioned!

My lab-side manner could charitably be described as ‘cautious’ – although ‘paranoid’ is probably closer to the truth. I am reluctant to take shortcuts in an experiment, for example, even when I suspect that it will make little difference. And I’m one of those annoying people who record their DNA concentrations on the tube as 1.998 micrograms per microliter instead of 2 – simply because the spectrophotometer is able to deliver readings to that level of fussiness.

Significant digits A Gilson P2 Pipetteman dialled to 0.165 microliters

This obsession extends to my pipetting. Yesterday morning, I did a few calculations and worked out that I’d need to add 0.165 microliters of an RNA oligo duplex to achieve the correct concentration. Of course I could have rounded to 0.17, because my trusty P2 is probably not that accurate, but I didn’t. (And yes, I brought the final volume up to 10 microliters with 9.835 microliters of water, though on a P20 instrument, the closest you can dial without microscopic vision is about 9.84).

I’ve always been like this. In school, I remember being affected very deeply by a math class discussion about precision versus accuracy: the classic illustration of the arrow-pierced bullseye target is still emblazoned on my long-term memory (see Wikipedia for a version of this). Even when I am cooking, I tend to measure water to the bottom of the meniscus in the measuring cup, and dry ingredients to two decimal places on our swanky digital scale. I may not always be accurate, but by God am I precise.

So is this behavior of any real value in the modern molecular biology laboratory, or is it all a sort of superstition? I guess I think that if you measure things carefully with the same instrument, all of your manipulations should be precise, if not accurate, on a relative scale. I know that there is no effective difference between 0.043 and 0.04 in practical biological terms for the experiments I’m doing, but it’s possible that my experiments are more reproducible as a result, and possibly more comparable when done on separate occasions.

I must confess, however, that I’ve caught myself relaxing a little bit on this point recently, for processes that I am pretty sure are fully robust. Only this morning I threw caution to the wind and diluted an antibody 1:100 in buffer by adding 1 microliter to 100 microliters instead of to 99. And I felt a lovely illicit little thrill in the process.

Sometimes you have to live dangerously.

There is nothing like coming back from an extended holiday to force you to take stock of your various research projects. This morning, after braving the iced pavements, flurries of snow and Underground carriages full of bewildered commuters who seemed, like me, to have lost their killer instinct after a few weeks of relaxation, I opened up my lab notebook and tried to remember just what it was that I had been so excited about on my last day. After a few minutes of desultory page-flipping, it was clear that I needed to collect my diffuse thoughts into one big List.

For me, list-making is a ritual event, but there is a definite activation energy barrier involved in getting down to it. So after morning coffee, I found myself engaging in what psychologists call redirected response behaviors. Like all the other cell biologists in the building, I made the new year’s pilgrimage to the kitchen and signed out a fresh bottle of medium, which I supplemented and filtered with great fanfare (after scraping a holiday’s worth of algae out of the suction traps). I thawed out cells. I cleaned off my bench and ethanol-wiped December’s orders from the white board. I chatted to people in the corridors who wanted to congratulate me about the effusive review)01571-7 of my novel in Cell. I took tea in the common room and listened to Martin Raff, our beloved professor emeritus, hold court in his characteristic Alan Alda drawl about the psychological motives of Bernard Madoff.

Finally, I could put it off no longer. The notebook was reopened and I doggedly wrote down headers for every minor project currently ongoing – about ten in all – before trying to scribble out exactly what remained to be done for each one. Although I’ve got plenty of loose ends to tie up for a manuscript, it was difficult to keep my mind from compassing in on the new exciting result. Soon I found myself faced with the need to shop: after a certain point, you need to know where your protein is expressed and what other protein partners it is flirting with. Although I am classed as a post-doc as far as the university is concerned, I am actually a Principal Investigator in the eyes of the Wellcome Trust, who have allotted me a generous consumables budget. The time had come: after a year of caution and frugality, I suddenly realized that the answer would come a lot more quickly if I finally got down to spending it.

Dear Reader, I did splash out on that antibody. What’s more, it felt damned good, and tomorrow, I sense that I will be spending even more.

Forget the Large Hadron Collider: there are scarier things afoot right here in the heart of Suffolk. If you hear news of a black hole yawning open a few dozen miles northeast of Ipswich, it was only me, trying to reheat a baked potato. (Hint: steer clear of the lower-leftmost button, the one that says “Chaos Defrost”.)

*Push the button:* Not just heat, but TURBO heat

Part of the fun of staying with someone else’s family for Christmas is working out the alien gadgetry. When it transpired that the serving of Christmas dinner was going to coincide precisely with the season finale of Dr Who, I failed utterly in convincing the ancient VCR machine (remember those?) to record. It wasn’t my fault, though: it seems the cat had taken to napping on top of it and crucial cables had been removed to forestall any unwanted electrocutions. But I did just about manage the male-oriented corkscrew, and aced all the female-safe white goods, including the breadmaker. The cooker was a bit of a bother: I loathe halogen burners, and it’s hard enough to get a turkey done to perfection without the oven temperature running about five degrees cooler than advertised.

Still, it wouldn’t be Christmas without a few tears before port and Stilton. I hope you all had a good one, and managed not to set your in-law’s kitchens on fire with the Christmas pudding.

The scientific method comes in many guises. During the past eighteen months in the lab, I have suffered from a severe lack of hypotheses. Or rather, I have been laboring under the umbrella of one very big, very broad hypothesis-with-a-capital-H:

Genes in the same pathway will often exhibit similar phenotypes after individual knockdown.

This idea may seem self-evident, but it comes with a corollary that turns out to have much more potential:

A novel gene that, when knocked down, gives a similar cell morphological phenotype to that caused by knocking down individual members of a known pathway, might play a role in that same pathway – especially if these changes are conserved in disparate species.

In other words, genes that lead to the same conserved biological end result will manifest similar effects when removed from the system, and unknown genes can often be placed into known functional modules by associating their phenotypes with those of known functional clusters. It’s a fine guiding hypothesis, but it doesn’t lend itself to yes/no testing in the way that I’ve been used to thinking about the scientific method. At least not on the day-to-day timescale.

So it is when you embark on a large, high-content genetic screen. You study hundreds of genes, instead of just one, and hope that something interesting comes out. Mine is nowhere near as big as many large-scale endeavors: whole genome sequencing efforts, for example, or Craig Venter’s sea microbe project. But I must confess that in many ways, it has probably been as tedious. As all my colleagues assemble pieces of their one-gene or one-pathway puzzles, lovingly filling in what scientists like to refer to as their ‘story’, I annotate images and compile statistics. If something looks intriguing, I have to force myself not to follow it up lest I get lost in a thousand wild goose chases. I remember studying the image of a particularly striking image of a cell on my screen, and a fellow post-doc asking me what gene I’d knocked down to produce it. When I told her it was yet another gene of no known function, she asked me what it looked like, what sort of domains the protein contained. When I told her I hadn’t even looked at the sequence, she was shocked. But there isn’t time: this is strictly big picture. You have to stifle your natural curiosity in the name of getting things done. It’s like having to make all your own toys, line them up on a shelf and inventory them before you’re allowed to play with a single one.

But finally, playtime is about to begin. Having finished my inventory and done a few validations, I’ve discovered an extremely interesting gene. When you knock it down in human cells, or its homologue in fly cells, the morphological changes that result are the spitting image of something very familiar indeed. And when you look up what this novel gene is, you realize immediately that there is something about what little we know of its structure and function that makes perfect sense as far as linking it in with this more familiar pathway. As all gene discoverers realize, it’s far more fun to work on a gene about which a little is known than to start from square one on a completely blank slate. Otherwise, it’s like embarking on a treasure hunt without the first paper clue in your hand.

And so it was that on Wednesday, my last day in the lab before the Christmas break, I was able to write my first real, day-to-day, hypothesis-with-a-small-h in my notebook:

It was, I admit, hard to leave work with this tantalizing blank waiting to be filled, but it will still be there, patient and unresolved, on my return in January. If there is one thing I have learned in my years in the lab, it is that the story is never finished – so you might as well enjoy your holidays.

Happy Christmas all!

My non-scientist colleagues are often surprised to find out that I sing in a band. Granted, ‘singing in a band’ might sound a bit more edgy than the reality: a bunch of aging scientists, ex-scientists, Nature editors and miscellaneous non-sciency friends who get together once a month or so to practice cover numbers for low-key charity gigs and the odd small festival and private party. It’s not exactly sex, drugs and rock-and-roll; although we do the rock-and-roll thing pretty well, the sex is entirely burlesque, in the form of a male percussionist who likes to dress as a nun with gold lamé disco boots, and the hardest drugs you’ll see circulating on stage on the night are Boot’s nasal spray and extra-strength Strepsils.

Frank-a-delic storms the Bullet Bar, Saturday

In fact, probably the closest we get to the real scene is in our practice space, The Premises in Hackney. The Premises is an anomaly and a great leveller: it’s both highly professional and extremely affordable. On its famous daily room-allocation board at reception, you can see who else is sharing the building with you at any given time. It’s always a kick to see the name of our band, Frank-a-delic, scrawled beneath the likes of The Arctic Monkeys, Razorlight or Lily Allen. People eye each other as they queue for tea in the attached café, trying to look cool and wondering who is famous and who is just a wanna-be. As you walk down the corridors, snippets of music leach through the sound-proofed rooms – tantalizing bits of every sort of style under the sun.

Should I be surprised that people are surprised I sing in a band? I suppose not. This is, after all, the same city that produced the following sneering précis in the daily science section of Friday’s London Metro:

I despair sometimes, truly I do. So that’s why I’m going to keep on singing.

In many B-movies, machines try to take over the world. And in real life, we often joke about losing our lab jobs to them. As case in point, three of my five years in graduate school were largely consumed by sequencing a few megabases of DNA. After performing the radioactive chain-termination reactions, I’d carefully clean and tape up the big glass plates, prepare the fresh polyacrylamide gel and run the samples through. When the dye ran off I’d dry down the gel and put it on film. Every day, there was also the previous evening’s film to develop and then – the worst part, as far as I was concerned – staring at this film, with its ladders of tiny horizontal black dash marks, and entering the sequences manually into the computer, running one finger upward as I went so I wouldn’t lose my place. After those three years, the G, C A and T keys on my computer were visibly faded compared to their neighbors.

Today, the latest production-scale sequencers can analyze millions of base pairs of DNA in less than a day.

Sobering, isn’t it? Viewed in this light, machines become the things that free up our time to do things that are a lot more creative. Back in the ’90’s, the only way to understand viral evolution was to roll up my sleeves and sequence strains of the same virus over and over, documenting the mutations that occurred in a population during the course of infection. But imagine if I’d seen the lay of the land in a few weeks, and could have spent the next three years probing into the question in more meaningful ways? How much more would I have achieved?

Of course one could argue that every generation has its tedious chore – for every megalithic task that has become routine, the latest state-of-the-art technique consumes our time in much the same way. I guess I’m living through this right now, as I do high-throughput RNA screens using only minor automation on five-year-old platforms and process hundreds of thousands of images visually. But I’ve seen the future (and have unsuccessfully dodged its o’er-enthusiastic sales reps): wardrobe-sized machines with robotic arms that do your entire screen with no human intervention. Indeed, they practically make you a cup of tea and nip down to the shops to pick up your dry-cleaning.

As far as the automated image analysis, it’s still early days with regard to the features that I’m interested in. But I found last week that the future lurks around that corner too. I can’t go into any detail at the moment, but let’s just say I’m involved in a collaboration with some computer scientists who are keen to try out their image algorithms on something completely different. Enter my dataset. We started simply, choosing one morphological characteristic of interest: the tendency of some of my gene knockdowns to turn fried-egg-shaped cells into vaguely geometric objects. Although the human brain can see this differences instantly, it turns out to be surprisingly challenging for a computer to make the same call. But this new algorithm, after a few rounds of training, managed the task with about a 96% success rate. And when I nipped over to the CS department to see where it had gone wrong, I was mortified to find out that my eye had misclassified some fried eggs as triangles, and the programme was actually 100% correct.

OK, this was embarrassing. But it was also fascinating, because the algorithm wasn’t looking at the same thing that I look at. All the pixel intensities had been isolated, plotted on polar coordinates, snipped into patches: strange random-looking patterns of light and dark that would not be out of place hanging in the Tate Modern. I am quite sure that whatever my visual cortex is doing, it is not seeing the data in this warped form. But nevertheless, the correct answer emerged.

I’m not looking for a new job just yet. But I might think about more creative ways to fill my time.

The bad news is that The Royal Institution has unceremoniously booted the Fiction Lab (our monthly science novel book club) out of its august halls for the entirety of December, during which the famous Christmas Lectures take precedence. The good news is that one of our number has organized a ‘rogue fiction lab’ instead – off site, and indeed completely off the lab lit mission statement.

So it is that tomorrow a group of us will be meeting in a private supper club in Soho to pick apart The Watchman, a classic graphic novel by Alan Moore and Dave Gibbons.

I used to devour comics as a child, but this is my first attempt at an adult graphic novel. I will admit it took a long time for me to warm to this book. The art, though striking, is a bit odd (too small of a head-to-body ratio, chiefly). There is a great deal of informative dialogue, and I thought the prose excerpts, though expertly written, were cheating a bit. Still, though I’m only halfway through, I’m definitely now sucked in. There are wonderful touches: intriguing flashbacks, flashforwards and other tricks with time and transition, and a dark streak of melancholy insightfulness that stays with you. The sole scientist character (Jon Osterman, a.k.a. Dr Manhattan) conforms to the usual boffin stereotype of aloof, inhuman and slightly out-of-control experimenter, but he is three-dimensional in other ways. Meanwhile, the creators of this story have a lot of things to say about the role of science in society.

Normal Fiction Lab service will resume in January (on the 12th) with This Thing of Darkness by Harry Thompson, a novel about the voyage of the Beagle told from the eyes of Captain Fitzroy. Just in time for Darwin 2009!

Last month I was asked to give a dinner speech for a Wellcome Trust/New Scientist shindig. A few days ago, when I was tidying up the house, I ran into the forgotten goodie bag that had been thrust at me on departure. Amidst the usual haul of marketing materials, pens and cheap gadgets, I discovered something truly intriguing: a sheet of science-y fridge magnet letters courtesy of the Trust’s broadcast division.

Attractive Cheap and cheerful public engagement magnets may inspire

“Science,” claimed the blurb on top, “is all about stories. Stories of the everyday as well as the extraordinary. See how many you can put together.”

An enormous amount of time-wasting ensued. This, I decided, was a fantastic way to stimulate people to think about the messy human endeavor behind the scientific profession. I was well stocked for lab-essential nouns like ‘experiment’, ‘research’ and the like, but there was a scandalous paucity of third-person pronouns and conjunctions. The most glaring omission was the word ‘scientist’ itself. Nevertheless, I finally managed to come up with a plot that would not be out of place in one of my own lab lit novels:

Any resemblance to any persons living or dead is entirely coincidental.