Category: Biology

Visualizing biological experiments

Video blogs are getting more and more interesting. This one, My JoVE, isn’t really a blog so much as a repository of valuable information for biologists, but it aspires to become a kind of video journal. JoVE stands for Journal of Visualized Experiments, and they’re trying to attack two big problems in biological research: “low transparency and reproducibility of biological experiments, … and time-consuming learning of experimental techniques.” Here’s their answer to the question: why a video-based scientific journal?

As every practicing biology researcher knows, it takes days, weeks or sometimes months and years to learn and apply new experimental techniques. It is especially difficult to reproduce newly published studies describing the most advanced state-of-the-art techniques. Thus, a major part of the Ph.D. and post-doctoral training in life sciences is devoted to learning laboratory techniques and procedures.

They are addressing two needs specific to the biology community, but they are picking up another one along the way: educating non-biologists and interested amateurs. You can find lots of experimental protocols online (see OpenWetWare), but these suffer from a few shortcomings: they use unfamiliar vocabulary, unavailable equipment, and they are often written in the stilted science-report prose that is beaten into all student scientists.

But like the how-to videos at instructables.com, these videos are delightfully conversational, and anybody can look at the shape of an Erlenmeyer flask without having to know the specific term for it. I am unlikely to buy an electron microscope any time soon, but I like to know what it looks like to drive one. I will certainly admit that watching someone use micro-forceps to invert the cuticle on a fruit fly larva and fish out the central nervous system is very far from knowing how to do it yourself. Still, it’s amazing how much those summer camp arts-and-crafts skills pay off in the lab.
(Spotted on the Sciencebase Science Blog)

Dodgy dogma and biology

Dogma is a funny word to appear so prominently in a science like biology. Any picture, any model, any theory currently in vogue is resting on the shifting sands of biological weirdness. I love, for instance, the fact that the Nobel Prize in medicine this year was awarded for major form of genetic regulation that nobody knew existed eight years ago.

A few weeks ago after I posted a link to some lovely molecular biology animations, my good friend Mike Onken made a comment that contained an oblique but cutting reference to the so-called Central Dogma of molecular biology. Since Mike is a certified Level 50 Molecular Biology Warlock at Washington University in St. Louis, I knew there was a good story behind that remark. I hounded him until he gave it up. “Everybody loves the Central Dogma,” I intoned. “It’s so dogmatic, and quasi-religious certainty is very sexy these days. What have you got against it?”

I got the response I was looking for, which I happily share below. Please allow me to present the words of Mike Onken:
Continue reading “Dodgy dogma and biology”

Molecular biology animations

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A few years ago, PBS ran a series called, simply, DNA. It included some of the spiciest, most inspiring animations of biological molecules in action that I’d ever seen. I longed to linger over them and savor them, but they came and went so fast in the show, and until this evening I had no idea who did the work. Over at information aesthetics I came across the 2006 infographics winners from Science magazine. One of these winners was Drew Berry of the Walter and Eliza Hall Institute in Melbourne, Australia. He’s the guy who made the beautiful animations.

Armed with this information, I was able to track down the mother lode in short order. Here is a page pointing to the QuickTime videos that gave me the shivers. May I particularly recommend the insane fruitbat circus otherwise known as DNA replication. If a Divine and Perfect Intellect is responsible the design of this unlikely contraption, somebody’s got a lotta ‘splainin’ to do.

Finally, here is an interview with Drew Berry about how he got the gig for the DNA TV series.

Freely transmitted neglected tropical diseases

The Public Library of Science has the laudable goal of making the world’s scientific and medical literature a freely available public resource. In the current sclerotic journal system, the flow of money greatly impedes the flow of information, and important scientific results are locked away behind expensive subscriptions. If you’re inside the privileged White Coat Curtain, you can find what you need. If not, good luck to you.

Another way that money skews medical publications is that editors consider diseases of the rich much more interesting than diseases of the poor. It’s surprisingly hard to fund and publish research about chronic infectious diseases of tropics. That’s not surprising given how markets work, but with the Internet we can do better now. Consider the case of the latest PLoS journal: Public Library of Science to launch new, open access journal on neglected tropical diseases.

Neglected Tropical Diseases (www.plosntds.org) will focus on the overlooked diseases that strike millions of people every year in poor countries, including elephantiasis, river blindness, leprosy, hookworm, schistosomiasis, and African sleeping sickness. The journal, supported by a $1.1 million grant from the Bill & Melinda Gates Foundation, will begin accepting submissions in 2007.

I can’t help but wonder if they will ever become so successful that they have to change their name to something like PLoS Reasonably Well-Known Tropical Diseases (not unlike questions on the Star Chamber RAQ list). Then again, if Al Gore is right about global warming, it might become PLoS Diseases We All Get Now That The Entire Planet Is a Hellish Fireball. It’s no joke that the tropics are coming your way, and they’re bringing their friends with them.

Cheap DNA sequencing

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This is a picture of one DNA sequencing machine: the Applied Biosystems 3730xl DNA Analyzer. It costs a few hundred thousand dollars and it’s starting to show its age, but it’s still the sweetest thing on the market if you want to sequence DNA accurately and fast. Here’s another DNA sequencing machine: RNA polymerase. It’s been around for a few billion years, and you’ve got trillions of them in your body right now, most of them sequencing DNA faster than the fridge-sized 3730xl. If not, you’d be real dead.

One of the reasons I’m optimistic about our ability to understand what’s happening inside the cell is that a cell is already a sophisticated information processing engine. If we can learn how to listen to it as it’s working, we won’t need to blast it to bits and paste its little smithereens back together in a kind of glorified biotech forensics lab. The violence of the language we use is telling. Polymerase chain reactions? Shotgun sequencing? Please. Why don’t we just ask that busy little RNA polymerase to tell us what it’s doing?

Of course that’s easy for me to say, but it turns out that’s exactly what Steve Block is doing in his Stanford lab. By stringing DNA between two tiny polystyrene beads, he can effectively listen to the sound of transcription and infer the sequence. The title of his paper drives home the fact that you can’t get much smaller than this: Single-Molecule, Motion-Based DNA Sequencing Using RNA Polymerase. If you don’t have a subscription to Science (which I don’t) you can read about papers like this in places like Alex Palazzo’s Daily Transcript and then you can go directly to the publishing lab for the paper (PDF).

The Inner Life of a Cell

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Someone I work with went to SIGGRAPH this week and posted a link to a cool movie he saw. SIGGRAPH (which stands for Special Interest Group Graphics) is the biggest computer graphics conference on the calendar, and it happens to be in Boston this year. Anyway, I followed this link and stumbled upon the juiciest, sexiest, most eye-popping movie I’ve seen all year: a speculative visit to the inside of a living cell.

Cellular Visions: The Inner Life of a Cell.

It’s sort of like the movie Fantastic Voyage, only from a molecule’s point of view. Starting on the outside of a white blood cell, you journey deep inside to gawk at some of the insane machinery that makes it work: a bubbling Golgi apparatus, actin fibers spontaneously spinning themselves from the soup, a lonely shuffling motor protein hauling its heavy-laden vesicle cargo up an endless microtubule footpath.

This is the movie I always wanted to make. From a protein’s point of view, the cell is an enormous place, and the process of building it is a mega-engineering project something like the construction of a skyscraper. Cartoony diagrams in biology textbooks just don’t transmit that sense of scale. You zoom through this cell, and you think, “My God! This thing is huge! Who’s in charge? What does that thing do?” The obvious question is: does it really look like that? The answer is a reasonably qualified yes, given their need to tell a visual story. Here is a quote from the press for the movie.

“There are plenty of others in the academic community creating these kinds of animations to illustrate concepts for students and their peers, but they tend to look and feel, well, very academic. The idea with this was to make something different, and there was definitely an effort to make it as cinematic as we could.” In some instances, that meant sacrificing literal accuracy for visual effect. “What we did in some cases, with the full support of the Harvard team, was subtly change the way things work,” Liebler says. “The reality is that all that stuff that’s going on in each cell is so tightly packed together that if we were to put every detail into every shot, you wouldn’t be able to see the forest for the trees or know what you were even looking at.”

I’m looking forward to a lot more movies like this. Proteins are very photogenic. You can see the full eight minute version of the movie (with scientific explanations and no cheesy music) at the XVIVO website. For the record, the process depicted goes by the name “leukocyte extravasation“. It’s not boy-meets-girl, but it’ll do.

Old school DNA purification

I often muse about the difference between the biology world and the software world. They’re ramming into each other more and more these days, and sometimes the result is more like a car accident than a gentle merger. Bioinformatics and systems biology are two rapidly growing fields where you are as likely to find a physics refugee bootstrapping a new career in biology as a biologist learning a few programming tricks in perl. The physicists and the biologists often betray their doubts about each other (as well as their own insecurities) to amusing effect.

One thing I know about software that works really well, though (you can see which side I come from), is how quickly well-written software tools can lower the barriers of entry to others that follow. For instance, I don’t need to write graphics primitives or web search engines, because someone else has written them for me. Even so, some people grumble… years ago a friend of mine complained that search engines were killing the joy he took in his skilled code hunting techniques using ancient tools like Gopher and Archie. I admire people who can chip their own flint spearpoints, but how nostalgic do you really want to be for a society of hunter-gatherers?

Given all this, I was entertained by this post on the Daily Transcript, a blog by cell biology postdoc Alex Palazzo. In a post about a product called Systems Biology Plasmid DNA Purification, he rips into those Johnny-Come-Lately’s who don’t know their protein assay from a hole in the ground. As he tartly puts it: “Now even a clueless Physicist can purify DNA without thinking about how this stuff actually works!” Ouch! Much better, though, was the comment posted by one of the blog’s readers.

Everyone is ripping on kits these days to prove how “old-school” they are. Look, you’re no Jacob Monod just because you make your own alkaline lysis buffers. You’re not a good scientist because you can isolate more DNA per cell than the other guy. You’re a good scientist because you can answer important questions quickly and definitively.

Well said. All those biology guys are just idiots who don’t get it.

Ooooh, I wish I hadn’t said that.

Synthesizing life

The Scientist web site has gone live with a new look, and as a result they’re making the entire site freely available for a few days. The bad news is that they will snatch this boon back under their subscriber walls in a few days. The good news is that their current cover story happens to be one of my favorite topics: synthetic biology. There is a well-written central survey article (Is This Life?) as well as some satellite pieces written by luminaries in the field. Drew Endy gives a good practical explanation of synthetic biology as a useful engineering tool, while Craig Venter and pals from his eponymous institute give a remarkably brief and lucid statement of the situation. They lead with this: “Synthetic biologists view the genome and the cell’s operating system.” And near the end, they say

One of our initial goals is to build a minimal cell. What is the least number of gene functions for a viable cell, in a defined laboratory environment? The question is of fundamental importance because practically every cell must have those minimal functions. When we fully understand this minimal set it should be possible to build a computer model that accurately predicts cellular behavior.

I’m used to engineers talking like this and being accused by responsible biologists of oversimplifying things, so it’s very appealing to hear biologists like Venter using this kind of language. The scenario he’s describing won’t happen fast, but it will happen, and it’s one of our best avenues forward. The scent of big game is in the air, and the hounds are off. Dozens of labs around the world are working the problem of minimal or synthetic life from as many different angles. It’s hard to say when something practical will come of it, but exciting science is churning out at a furious rate. Maybe we need to dangle one of those DARPA Grand Challenge carrots. If we work it right, we can arrange it so those crazy post-docs don’t get any sleep at all.

Dirt vaccines

I knew it would come to this: dirt is officially good for you. The “hygiene hypothesis” has received another shot in the arm in a recent talk by Professor Peter Openshaw of Imperial College, London: How ‘Dirt’ Could Educate The Immune System And Help Treat Asthma.

What is the hygiene hypothesis? It’s the idea that being exposed to filth early in your life strengthens your immune system, whereas being constantly scrubbed clean by anxious parents merely sets you up for a clock-cleaning viral sucker punch. Your wimpy little immune system will never know what hit it. The same hypothesis explains why polio’s awful bloom happened alongside the rise in modern plumbing. As Jane Smith says in her book Patenting the Sun: Polio and the Salk Vaccine

Put simply, paralytic polio was an inadvertent by-product of modern sanitary conditions. When people were no longer in contact with the open sewers and privies that had once exposed them to the polio virus in very early infancy when paralysis rarely occurs, the disease changed from an endemic condition so mild that no one knew of its existence to a seemingly new epidemic threat of mysterious origins and terrifyingly unknown scope.

As I’ve mentioned before on this site, drinkable pig parasites (i.e. barnyard filth) are now being used to combat Crohn’s disease. And now, Professor Openshaw is telling us that the alarming rise in asthma may be due to the same cleanliness your mother so cherished. However, “having many older siblings, attending day care at an early age, or growing up on a farm can help in promoting resistance to disease.” Eventually our best vaccines will consist of finely tuned warmed-over sewage.

The fruits that civilization has given us, boons such as high-fructose corn syrup, Wonder Bread, partially hydrogenated cottonseed oil, and now personal hygiene, we must eventually surrender in the name of robust health. Take two mudpies and call me in the morning.

Hacking life

Why is molecular biology so different from engineering?

Engineers build things using well-understood systems, the details of which, while sometimes complex, were originally specified and documented by other engineers. Molecular biologists, on the other hand, are uncovering the bizarre workings of an almost impossibly remote alien world hidden from all but the most obsessively persistent observers.

By great contrast, a field like software can be up-ended with lightning speed by a clever teenager, because the tools are smaller, cheaper, easier to wield, and also because people need only download and run software to understand its value. The next Netscape, Napster, or Google might be right around the corner.

Biologists, on the other hand, devote endless hours to coaxing new information out of living cells. It can take years of lab-bound tedium to reach a result which may, after all, turn out to be inconclusive. Results, once published, may take years to verify. Consequently, biologists tend to move in conservative, reputation-oriented packs. When biologists publish, they know it is critical to publish in a journal that has “impact factor”, since findings can be so easily questioned. Reputation is the currency that can validate their findings. In many ways, biologists function more like the members of a medieval guild than the participants of a fast-moving twenty-first century knowledge industry.

Nevertheless, biology is changing. It must, and it will, move from its current mode into more of an engineering mode. Industrial-scale genomics and systems biology are the beginning of this transition. What is coming? Here’s a short list:

  • cheap, fast experiments
  • easy, accurate simulation
  • easily verified results
  • an information-sharing “hacker” culture

All these things are common in the engineering world. Of this list, the last item is the most important and will certainly be the slowest to change. In biology, the toys have been too expensive, the results too dear to be profligate in giving them away. If you devote your entire career to a single protein, for example, how likely are you to be generous with what you find? So biology culture has moved slowly on the backs of laboring grad students. One of the great turning points in bio-engineering came when Craig Venter ushered in the era of industrial genomics. Up to that point, the cost of decoding a genome was dominated by human labor. The attitude was essentially: “What’s the rush? There’ll always be more grad students to finish this in another decade or so.” High-speed machines changed that equation forever.

I have been very happy to read dispatches from the front lines of biological research that indicate the age of the bio-hacker is upon us. The notion of a “bio-hacker” can sound alarming, I admit, but things are going to start happening extremely fast. Here are some items: Howard Salis’ synthetic biology blog has a good post on automated molecular biology that touches on these themes. Bio-IT World has a couple of exciting articles, one on a breakthrough genome sequencing product and another on whole-genome synthesis entitled “Pimp My Genome”.

Pimp my genome. Heh.

Now that’s what I’m talking about.

Update. Over at Nodalpoint, the bioinformatics weblog, Pedro Beltrao just made a very similar point: “Open source software comes to mind as one of the best examples of what you can achieve by getting interested people together in a virtual space. Why can’t we do the same for scientific research?”