Self-referentiality in cell signalling

”This title is false”

Thus begins a reflection in the April 23 issue of Nature, by Mark Isalan and Matthew Morrison. They are alluding to Epimenides’ paradox, the famous philosophical concept where a statement, if true, must be false, and if false, must be true. (The paradox is usually related in the form: All Cretans are liars, as Epimenides himself was from Crete.) As Douglas Hofstadter so brilliantly exposed in his canonical book “Gödel, Escher, Bach”, this same phenomenon underlies Gödel’s incompleteness theorem. In effect, if a mathematical system is “complete” and able to incorporate such phrases as “this theorem is false”, it will therefore contain self-contradictions. 

Statements referring back to themselves occur very frequently in biology, if you take a broad view of information transfer. For example, many cell signalling molecules induce an inhibitor of their own activity, in a negative feedback loop. What Isalan and Morrison highlight is the need to envision such systems not in the familiar two dimensions, but over space and time.

Consider the following ostensibly simple system:

It looks quite straightforward: p53 induces MDM2, which in turn inhibits p53. But can you predict how this system will behave?

A number of possibilities present themselves. Is there a steady state, where the two molecules are at equilibrium? Is there, perhaps, a constant slow decline of p53 until there is no activity left? It’s even imaginable that p53 could be completely uninducible in a system corresponding to the picture above.

In fact, p53 oscillates very dynamically when it is induced. It is thought that the number of peaks, rather than their amplitude, determine signalling intensity. This was only discovered fairly recently in Galit Lahav’s laboratory at Harvard.

The former president of the Karolinska Institutet, Hans Wigzell, often likens reaction pathways like the one above to “Donald Duck biology”. They present a tremendously oversimplified view of the system in question, by omitting time, space, and weighting of the processes involved.

With the rapidly increasing possibilities of resolving molecular interactions in time and space, we will have to get used to abandoning simplified models in favour of more complicated representations. I wonder how long it will take before differential equations are required knowledge for biology undergraduates?

The Scientia Pro Publica blog carnival is up

The sixth edition of the Scientia Pro Publica blog carnival is hosted by Kelsey Abbott at the Mauka to Makai blog. Among the rousing stories of sex, drugs, cannibalism, phylogenetic classification, and sheer madness, you will also find my recent post on Open Access publishing.

Head over there and have a look!

Who is the woman in your relationship?

For some, it’s a bitter fight. Check out this video of two flatworms mating!

The first one who gets stabbed by the other’s penis will become the mother, and both are struggling with gusto and determination for the fatherhood.

Hat tip: Deep Sea News.

My research is published with Open Access!

My latest paper has just been accepted for publication in the Journal of Experimental and Clinical Cancer Research. This is an open-access, online-only scientific journal. When the paper comes out I will cover it in another post. Meanwhile, let me exhort my fervent commitment to open access scientific publishing.

The cycle of scientific endeavour typically goes like this (substitute your favourite researcher if you want):

1. Somebody gives me money
2. I do research
3. I write up the tattered remnants of my grand designs into a decent manuscript and send it to a journal
4. The journal sends the paper off to other scientists who review it for free, while I review papers from other scientists in other journals in my spare time because of loyalty to the Scientific Endeavour or something
5. The journal decides, hopefully, to print it and then charges me at least 1000 USD for the luxury. It also charges subscribers and university libraries fo the right to read the article in print or online, making it impossible for anyone outside the system to access the knowledge I have painstakingly assembled.
6. The Cancer Fund or the NIH (substitute your favourite funding body) counts my journal articles and then, hopefully, gives me more money.

While both I and the funding bodies (which are often backed by public tax-money) want the results to be as accessible as possible, the lock-in behind paywalls becomes an unfortunate consequence of the fact that journal article are nearly the only metric of achievement by which I can be measured.

Furthermore, I need access to all the journals in my field. It’s not the case that one could simply be substituted for another. This means that my university is almost completely price-insensitive, a situation upon which the scientific publishers have been quick to capitalise. Elsevier, one of the “Big 3″ together with Springer and Wiley, has had an operating profit margin above 35% in recent years in the science and medicine section of its business.

A recent industry report (not online) from Deutsche Bank on scientific publishing states that “We believe the publisher adds relatively little value to the publishing process.” This is true. The value added lies, besides the typesetting, mainly in that the credibility of the research can be boosted by the strong brand of a prestigious journal. And I don’t have to add that that sort of bias in the scientific community is a problem even though some may benefit from it.

A bunch of corporate behemoths are making obscene amounts of money by keeping (mainly) tax-funded research results out of the public domain. Outrage is warranted.

The solution? Open access publishing, of course!

There are a few different models for open access, including self-archiving of manuscripts and data on public servers. But the simplest and best-functioning solution, in my humble opinion, is the open access journal. It’s just like an ordinary journal but with free online access for everyone. The costs of publication are covered by a fee (again, around 1000 USD) payed by the scientists themselves (us).

The health worker whose hands are in the foreground will be able to read my latest article online without a subscription, should he/she want to.

The cost is not greater than for many traditional journals, and is offset by the greater availability of the article. Some studies suggest that open-access articles are cited at least twice as often, at least in certain fields. But most of all, there is an imperative stemming from our purpose as scientists to generate knowledge and actively share it around the world. We have no reason to keep supporting the self-serving oligopolies of knowledge that still publish most scholarly articles, when we can instead make them freely available to the entire world.