Fun with Proteins

I think almost anyone who has studied protein 3D structures would agree that it is a hard problem.

For the uninitiated, proteins are made out of chains of amino acids. Each amino-acid consists of a backbone and side-chains. The properties of the side-chains determine the structure that the chain will take on in 3D. For example, polar side-chains may repell each other, and hence tend not to be close. Another example is hydrophobic ("water-fearing") side-chains which need to be on the inside of the protein, away from the water molecules that surround a protein inside the cell.

There's more than one way to determine protein 3D structure. You can take the actual protein, crystallise it, shoot x-rays at it and work out the structure from seeing how the x-rays diverge. Or you can take all of the contraints mentioned above, encode them in a computational model and get a computer to crunch the numbers for you until it finds the optimal structure.

Or, well, you could just get people to do it by hand. For free. And have fun while they're doing it.

That's the principle behind FoldIt, a new game based on, yes, you guessed it, protein structures. The idea is that protein folding is much like a puzzle, and people love doing puzzles. So we let them fold virtual proteins, and evaluate the structures based on the constraints that we know about. Add some fun sounds when you're tugging and dragging proteins, a bonus for reducing the number of moves starting from the initial configuration, and an element of competitiveness in the form of an online ladder, and you've got a fun little game that people will actually want to play.

FoldIt is currently in open Beta and completely free to play. I've tried it out, and it really is a lot of fun. The online option allows you to chat with fellow folders while you're playing, and the interface is simple and intuitive. You don't even have to know anything about proteins; there's a very easy tutorial to get you up to speed, and you'll figure out soon enough what works and what doesn't.

It will be interesting to see if FoldIt players can come up with better protein foldings than a computer could. FoldIt is not the first instance of a "useful" game I've come across. I first heard about the concept, called human computation, in the context of a game called ESP that gets its users to label images with text. It makes you wonder what other arduous bioinformatics tasks we could turn into games (gene-finding anyone?).

A Cautionary Tale

Remember the asteroid that's coming close to hitting the earth in 2036? Most of us probably heard about it at some point or other, made a quick calculation to see if we would be alive then, and forgot about it. If you looked into it a bit further, you found out that NASA only gave it a 1 in 45000 chance of hitting the earth; not nearly enough to worry about.

But then, shock! horror! what if NASA were wrong? People make mistakes. It's not as if they double-checked these results.* And it's not as if the smartest minds of the planet were working for NASA.** Who could we rely on to find out if there are any problems with NASAs calculations? Oh, I know. Let's ask a 13-year old schoolboy. It's good enough for The Times. And what do you know, the whiz kid places the risk at 1 in 450. Definitely in the "we should worry about this" category.

Except NASA never confirmed it, as stated in that article, and has in fact since denied that the boy's calculations are correct. Mark over at Good Math, Bad Math has a simple explanation why his assumptions are flawed.

I don't mean to put down Nico Marquardt, the boy who made the calculations. He obviously put a lot of effort into this, and it must have been pretty good work to convince so many people. Who I do want to put down is the many many papers who simply picked up this story, based on its "newsworthiness", seemingly with no fact checking at all. One phone call to NASA would have cleared it all up. Is this all we can expect from Old Media?

* They did.
** They are.

Open Reviews?

The PLoS Computational Biology journal has an editorial about open access biology papers. Most of it is the usual Web 2.0 aspirations: We need more structured data, more semantics, more killer apps taking advantage of it.

Not that I disagree, necessarily, but I've heard it all so often that it's not really registering anymore. Maybe the killer apps will come along, and maybe they won't. Web 2.0 thinking has potential for science publications, but not everything that has potential gets realised.

But towards the end of the article, there was something that caught my attention: Open review.

Certainly rating a paper would seem reasonable when done by the Faculty of 1000 (http://www.f1000biology.com), but it is not a generally accepted practice. We challenge you to rate this Editorial too. In some ways the reluctance to rate a scientific paper is strange since we suspect the same person may well rate a book on amazon.com. Another option would be to add a Digg or del.icio.us button (http://digg.com or http://del.icio.us) to incorporate conventional media ranking tools into an academic journal Web site. If one finds an interesting article, one could immediately flag it with these tools.

Now this is interesting, because peer-review is a nearly sacred notion in science. Your paper has not proven merit until it has passed the peer-reviewing process and been published. It basically says, "other scientists thought this was worth reading".

So what happens if the reviewing suddenly become open to all? Well, it essentially become a popularity contest. Digg is a perfect example: The stories that end up on the front page are the ones that a lot of people liked. Very democratic, isn't it? Only it means that today the stories included "Pranks to pull on your Co-workers" and "The 10 Most Mismatched Movie Couples".

Oh, there were plenty of interesting stories as well, but my point is that what's popular is not necessarily what's best. By all means, let people comment and review papers, but make sure we know which reviews come from scientists, and which come from your average schmoe. I know it sounds elitists, but it's not much more elitist than demanding that the person who takes out your appendix have a medical degree.

History in our Genes

Via the Wired Science Blog, I found this story about a study of variations in the human genome among different populations. While this has been done before, the new study shows how much data we can get just by looking at people's genes.

"The novel finding is the depth of the resolution we've gone to," said National Institutes of Health neurogeneticist Andrew Singleton, co-author of one of the papers in Nature. "This really lets you start moving towards locating individuals geographically. Previously, we've been able to look at the genome and say, 'This part is from Africa, this is from Asia. Now we can look past that and say, 'It's from this part of Africa or Eurasia.'"

Continued Singleton, "We can use these data to look at other areas of the genome that might have been under particular pressure for survival, and go from there to figuring out what the pressure is. One area that was highlighted was the genes responsible for digesting lactose. In countries where there's milk consumption, that one particular haplotype that allows more efficient lactose digestion has arisen."

They've not only been able to identify populations based on the genome alone, but they've also managed to model how humanity spread around the globe. Our history is encoded in our genes. How cool is that?

And all this was done using only the genomes of about a thousand people. Imagine what will be possible once we have even more data. And on the biology side, we will be able to repeat the same analysis for animals or plants. These are truly exciting times.

The full article that appeared in Science can be read here.

Evolving Evolution

Okay, that title was too easy a pun. I apologise. But Wired blog had a couple of posts about where evolution (as in, "the theory of...") may be headed. The name for this extension of evolution is complexity theory. I bet that's going to be confused with chaos theory a lot.

What is complexity theory? Let's let Wired explain:

Not a religiously inspired revision -- intelligent designers need not apply. Nobody suggests that genetic mutation and natural selection aren't responsible for the evolution of birds from reptiles or humans from tree-swingers.

But a growing number of scientists do say that neo-Darwinian evolution doesn't explain certain jumps in biological complexity: from single-celled to multicellular organisms, from single organisms to entire communities.

The jumps -- saltations, in complexity parlance -- appear to be non-linear emergent phenomena, the result of networked interactions that produce self-organization at ever higher levels. From this perspective, Darwinian evolution is a mechanism of a higher universal law, perhaps even a variant on the second law of thermodynamics.

There's something that will strike fear into the hearts of mathematicians and computer scientists everyhwere: non-linear emergent phenomena. Everybody knows that that is the last thing you want to be modelling.

Personal fears aside, this seems like a reasonable extension. It is important to find out how certain networked properties emerge, whether they be multi-cellular organisms, or human societies.

Now, some people, including me before I read this article, might think that classic evolution might be all we need to explain these jumps. Just because we haven't figured it out yet, doesn't necessarily mean that we need a new framework, right?

Maybe, but the second Wired article that caught my eye gives more evidence that our current view of evolution may limit our ability to explain certain phenomena.

When Guy Hoelzer runs computer simulations of organisms living in the modeling equivalent of a featureless plain, he sees them break into different species -- even though there's no reason for natural selection to take place.

That preliminary but tantalizing finding hints at some larger phenomenon driving the mechanisms of neo-Darwinian evolution. Hoelzer thinks the phenomenon is self-organization: combine energy with complex networked interaction and order will emerge.

As with all experiments based on simulation, you have to take this with a grain of salt, but it's certainly more fodder for complexity theory.

One thing I don't quite agree with is that they try to relate it back to the second law of thermodynamics. ("The entropy of an isolated system not in equilibrium will tend to increase over time, approaching a maximum value at equilibrium.") That seems doubtful to me (speciation is entropy?) and also a bit premature. Save the unification with physics for when you've worked out the details of your theory.

It's Started Already

Remember the "telepathic" DNA story? Well, what'd I tell you:

DNA Found to Have "Impossible" Telepathic Properties

[...]No one knows how individual DNA strands could possibly be communicating in this way, yet somehow they do. The “telepathic” effect is a source of wonder and amazement for scientists.

So we've moved from a "telepathy-like quality", that can be explained, to "impossible telepathic properties". I predict that we'll reach alien influences in two more steps.

Interesting Article, Bad Title

LiveScience had an article about a recent discovery in genetics made by some researchers in Maryland. They found out that DNA sequences that are the same are more likely to cluster together than those that are different.

Curiously, DNA with identical sequences of bases were roughly twice as likely to gather together as DNA molecules with different sequences.

[...]

The electrically charged chains of sugars and phosphates of double helixes of DNA cause the molecules to repel each other. However, identical DNA double helixes have matching curves, meaning they repel each other the least, Leikin explained.

It's an interesting discovery, although it remains to be seen how useful it's going to be. But that's not the reason I'm mentioning it here. What made me laugh was the title they gave the article:
DNA Molecules Display Telepathy-like Quality.

How long until the first New Age healer picks up on this and claims he can heal your DNA by telepathy?

Google's Newest Invasion

Having cornered the search market, taken over Youtube and struck fear into the hearts of publishers, Google is licking its lips and looking for new targets. Next stop, Wikipedia.

The potential Wikipedia killer app that Google is developing is called knol, and it has of course sparked much discussion in the blogosphere, with bloggers outbidding each other in who can come up with the wittiest pun. (My favourite: Google Sets its Guns on the Grassy Knol). But puns aside, should Wikipedia be worried? Should we?

Yes and no. You have to remember that Google does not always suceed. Remember Google Video? That didn't take off. Google News? I don't know any News junky who uses that. And I don't see people rushing to pick up Google Talk.

Knol operates on a completely different model from Wikipedia. Instead of having a page for a topic that everybody can edit if they think they know better than the original author, in Knol, the author controls the content, and other users can only suggest changes. Also, you could have more than one "knol" on each topic. Google assures us that more popular (and hence, presumably, more accurate) knols will float to the top, but will they really?

Of course, you have a similar problem in Wikipedia, but it's mitigated because you can correct information: In knols, it seems you can only decide if you like the information or not.

Then there is the problem of orphaned topics: What happens if a "good" knol is abandoned by the author? Can we reuse it to start a new knol? Or is that information frozen in time forever, neither to be reused nor updated?

There are tons of problems that could bring knols to its knees. Of course, there are also reasons why it could succeed: There's less risk of vandalism like Wikipedia has seen, and there are more incentives for people to contribute (Google has agreed to share ad revenue if knol owners let them place ads on their pages).

Whether or not knol succeeds, I believe that the two models are different enough that they could even exist side-by-side. After all Encarta and the Encyclopedia Britannica both sold copies, didn't they?

Pay Per Use Bioinformatics Software

Equinox, a company based in London and started by the Imperial College, has started offering access to some of its bioinformatics tools on a pay per use basis. Basically, they host the software on their servers, and you pay them each time you want to run a query. Their flagship product has to do with protein structure prediction:

The first product available will be Equinox's leading Phyre(TM) homology modelling and fold-recognition software. User research has shown that proteomics is an ideal target market with positive feedback from research, biotech and pharma audiences.

Yadda, yadda, the press release goes on to state how great this all is. Of course my knee-jerk reaction was: "Pay? Nevah!" But then I realised that you'd have to pay anyway. Previously, this product had only been available via a software licence. Now, that's fine for big companies and universities, who use it frequently. I suspect most of them will stick with the licence as well.

But for smaller companies, or an isolated researcher who may only need to use the software once in his career, the Pay Per Use model may actually have an advantage. Of course, it would be preferable if they'd offer the tool for free, but what kind of business model is that?

Unfortunately, I couldn't find out what the actual price per use was, or how it compared to the cost of a licence. How many uses before a licence would be cheaper? They need to get the balance right, otherwise people will opt for licences every time, and the PPU idea might well die a premature death, as far as bioinformatics is concerned.

Meanwhile, if you want to play around with a bare-bones version of Phyre, you can still go here. Just put on your academic hat first.

Undergrad Proves Important Theorem

I read on the Wired blog that a 20-year old engineering student from the University of Birmingham has formally proved that a certain Turing machine model invented by Stephen Wolfram* is the simplest possible model.

Turing machines, for those not up on their theoretical computer science, are simple computing machines that Alan Turing conjectured were capable of calculating any computable function (he didn't say anything about efficency).

The usual model is that of a machine with a ticker tape with a sequence of symbols and a number of states. The machine looks at the tape one symbol at a time, and, depending on the symbol and its current state, decides what to do: Go forward one character, go back one character, overwrite the current character, or change state.

What makes this minimal Turing machine special is that it only has two states and three different symbols (sometimes called colours). The student proved that if you take away a colour or a state, it wouldn't be a Turing machine anymore.

Meanwhile, what important result did I discover during my time as an undergraduate? Oh, that's right, I discovered that you can live on nothing but pizza for a week...

*Yes, the same one who created Mathematica.

No, I'm not Dead

Just busy. It appear that while I was trying to catch up to uni work (imagine a hamster in a wheel, running as fast as he can, always convinced that he will get there eventually), Al Gore won the Nobel Peace Prize.

Now, some people are wondering why he won. There's two responses for that.

First, there's nothing more important to peace than stopping global warming. Pandagon has a more elaborate explanation of this point than I'm willing to give.

Second, get some perspective. The Nobel Peace Prize has gone to Yasser Arafat before, and you're complaining about Al Gore getting it? Now, if they were giving it to George Bush, then you'd have something to complain about...

Skynet can't be far off...

From the scary side of AI comes this report from Wired: The US government is sponsoring research into tracking terrorists on the Web. Now that might sound innocuous, but according to the article:

The University of Arizona's ultra-ambitious "Dark Web" project "aims to systematically collect and analyze all terrorist-generated content on the Web," the National Science Foundation notes. And that analysis, according to the Arizona Star, includes a program which "identif[ies] and track[s] individual authors by their writing styles."

That component, called Writeprint, helps combat the Web's anonymity by studying thousands of lingual, structural and semantic features in online postings. With 95 percent certainty, it can attribute multiple postings to a single author.

From there, Dark Web has the ability to track a single person over time as his views become radicalized.

The project analyzes which types of individuals might be more susceptible to recruitment by extremist groups, and which messages or rhetoric are more effective in radicalizing people.

You can probably imagine what would happen if Writeprint were used to track down real terrorists and made a mistake. Better not type to heatedly in those flame wars. And stay away from "they set us up the bomb" jokes!

I'm not condemning the research as such: The idea of being able to tell who a certain text was written by is fascinating. But the application is worrisome. If this ever becomes a viable tool for counter-terrorism, it should be very strictly controlled.

The Wired article focuses on Writeprint, but a quick look at the website for the Darkweb project shows some more interesting projects:

The Terrorism Knowledge Portal is a search engine created specifically for the domain of terrorism research. [..] It aims to explore governmental, social, technical, and educational issues relevant to supporting intelligent Web searching in terrorism-related research. The portal supports searching of a customized terrorism research database with over 360,000 quality pages. In addition, it provides access to terrorism research institutes, government Web sites, news and presses, and a collection of useful Web resources for researchers.

A terrorism search engine? When is Google getting in on this?

A computer-driven natural language chatterbot that will respond to queries about the terrorism domain and provide real-time data on terrorism activities, prevention, and preparation strategies.

Real-time data on terrorism activities? Good luck with that.

Finally, to close on a lighter note, the Wired article quotes the National Science Foundations on some of the risks of the project:

"They [terrorists] can put booby-traps in their Web forums," Chen explains, "and the spider can bring back viruses to our machines." This online cat-and-mouse game means Dark Web must be constantly vigilant against these and other counter-measures deployed by the terrorists.

Right. Because obviously you instruct your spider to download any file it finds to your servers, execute it and maybe display a skull logo on your monitor as well while the virus deletes your files. I understand your desire to make your work sound glamorous by phrasing it in terms of a battle, but please don't pretend you don't know about basic security procedures.

Breasts on Facebook?

Brace yourselves. What I say next may shock you. Ready? Okay:

There were breasts on Facebook.

Don't panic! Breathe. Stay with me. The good news is, Facebook acted decisively and removed ALL of the...

Wait, hang on.

Okay, I'm being told they didn't remove all of the pictures of breasts. Apparently, they removed pictures of a woman breast-feeding and banned the woman in question from Facebook.

Now, even most prudes would find it hard to condemn breast-feeding as obscene. See, contrary to popular (read, male) opinion, breasts actually serve another purpose besides being sexually arousing. In deleting the pictures, Facebook was focusing on the nudity of said breasts, and many commentators are making the same mistake. Instead of saying "Facebook deletes pictures of woman's breasts", how about "Facebook deletes pictures of woman feeding her baby". That's all that that picture was about, a baby being fed. How much more innocuous can you get?