The great ideas of biology

The guardian has a series called “It’s a small world“, among which is a video called “Gregor Mendel and the genesis of genetics” where

Nobel laureate Sir Paul Nurse tells the story of another great idea in biology – genes as the basis of heredity – in a lecture at the Royal Institution in London. It all started with the gardening monk Gregor Mendel and his peas in the 19th century and reached a key milestone with the unravelling of the molecule of heredity, the DNA double helix, by James Watson and Francis Crick in 1953

The great ideas of biology covered are

• the cell
• the gene
• natural selection
• Life as chemistry
• Biology as an organized system.

Similarly to “A Brief Introduction to Genetics” David Murawsky (as mentioned around here before, but hey, they repeat stuff on TV all the time, and not only the goodies) put another impressive clip out there: “18 Things You Should Know About Genetics“. Enjoy!

Kendrew’s prediction – are we there yet?

Indeed, in the very long run, it should only be necessary to
determine the amino acid sequence of a protein, and its three-dimensional
structure could then be predicted; in my view this day will not come soon,
but when it does come the X-ray crystallographers can go out of business,
perhaps with a certain sense of relief, and it will also be possible to discuss
the structures of many important proteins which cannot be crystallized and
therefore lie outside the crystallographer’s purview.

(JOHN C. KENDREW “Myoglobin and the structure of proteins” Nobel Lecture, December 11, 1962)

If you are into (structural) molecular biology, you will probably have seen this before. Honestly, I don’t get tired of reading this statement. That was 49  years (and 11 days, to be precise) ago – where are we now, almost half a century later? Are we there yet? (sounds like the little ones nagging on a long-distance journey – daddy told you it would take a while!) Seems we might be there soon, since we have made quite some headway recently.

First of all, the above statement displays some amazing farsightedness combined with a humble self-perception. He is not overstating it, indicating that not all will be crystallized. If you read on in his speech, he was already talking about larger assemblies and complexes, and that’s where we are now, and that’s where things get REALLY interesting. Besides the picture with him modeling a 3D structure (on the sticks for z axis) is by no means old-fashioned, to me it means he just took what was available at the time to get the 3D model constructed. Today we have sophisticated ComputerGraphics, yet nothing beats the experience of building a physical model – an art that should not be forgotten and developed further (thinking of 3D printing here). I am convinced that even in the age of the high-throughput techniques, interaction data etc. we ultimately need a structural view to truly understand the molecular mechanisms.

But the main point – or prediction – is that ultimately, we should be able to compute structure and function from sequence alone.

If you think about it, that’s a very bold statement indeed, with wide ramifications. By now our sequencing capabilities are growing at a pace beyond Moore’s law (see here). I probably don’t have to remind ourselves that experimental structure determination is difficult and time-consuming, to say the least. And computer predictions in the absence of a related solved structure in the PDB are usually no match for the real thing (a.k.a. experimental 3D structure).

But there is a fresh breeze in the field: Recently a number of groups report that the ancient dream (from the mid-nineties and even before, “ancient” in bioinformatics = over 15 yrs) of using patterns of correlated mutations to derive useful spatial constraints for structure prediction does work indeed. Properly. Finally!
Given enough information content, seems there are no limits to the size of the proteins, and even notoriously difficult ones like transmembrane structures seem to work. All you need is sequences. And lots of them. Properly aligned, of course. (That’s what a lot of bioinformatics was all about, wasn’t it?) But massive amounts of sequences is what we get anyway these days, more than you ever wanted (to analyze) from next-gen sequencing projects. That’s off-topic, delving deeper into that mania is a topic for different post to explore.

If you are interested to check it out in depth: One of the methods is called EVfold, see http://EVfold.org.

Of course, there is still some room for optimization, cross-fertilization and improvement in the methods, I think. Simply by looking at some of the predicted contact maps, it’s fairly obvious to me these methods are not only better than what was available so far, but they are also not identical. Seeing their performance and following the competition in this field hotting up on next years CASP will be jolly exciting.

I’m sure I’ll keep you posted on further developments and deeper analysis – for the moment I’ll leave you with a few references to get started. As a final word, I am so glad most of them (at least the ones I list below) are not hidden behind a payhedge but open access, free to check-out by anyone who cares.

Enjoy!

References:

1. Marks DS, Colwell LJ, Sheridan R, Hopf TA, Pagnani A, Zecchina R, Sander C. (2011) Protein 3D Structure Computed from Evolutionary Sequence Variation. PLoS ONE 6(12): e28766. doi:10.1371/journal.pone.0028766
2. Taylor WR, Sadowski MI (2011) Structural Constraints on the Covariance Matrix Derived from Multiple Aligned Protein Sequences. PLoS ONE 6(12): e28265. doi:10.1371/journal.pone.0028265
3. Burger L, van Nimwegen E (2010) Disentangling Direct from Indirect Co-Evolution of Residues in Protein Alignments. PLoS Comput Biol 6(1): e1000633. doi:10.1371/journal.pcbi.1000633

The Joy of Stats

Visualisation is right at the heart of my own work, too […]
and I know, having the data is not enough.
I have to show it in ways people both enjoy and understand.

Hans Rosling’s TED talks have been a shining and influential example to many (including myself, I hope) – here is him condensing the development of the last 200 years around the globe into an engaging presentation in just under 4 minutes.

Hans Rosling’s 200 Countries, 200 Years, 4 Minutes – The Joy of Stats – BBC Four – shared by Hyun P. via the group Wolfson College, Cambridge on LinkedIn.

More links and the full (1h) documentary on BBC Four are available here and on the Open University website. Also, there is an interview and a best-of video on wired.com.

“I kid you not, statistics is now the sexiest subject on the planet” says Hans Rosling – I guess the title is a (not so subtle) reference to the 1972 book from Dr. Alex Comfort.

Ancient computing – the Antikythera Mechanism

When diving deeper into the far end of the historic roots of bioinformatics, I came across the Antikythera mechanism. To me, it has all the hallmarks of what bioinformatics is about: taking in the available knowledge of the time, integrating all the data there is into a functional machine model that actually makes useful and verifiable predictions. And all of that already happened approximately 2100 years ago. Wow!

The timeline for BioInformatics I created however did not seem to accept a corresponding entry, although on dipity dates B.C. should work (since April 2011, they say) – but not for me (yet).

R-omes aren’t build in a day

where R ∈ {Prote, Interact, Gen, …}

Tommy Carstensen

[…] built a model of DNA out of LEGO bricks (of PDB entry 2DAU, to be precise) to celebrate the 40th anniversary of the PDB. The clip also has educational value, explaining some of the basics of DNA structure and more.

[posted by Gerard J. Kleywegt via pdb-l mailing list (pdb-l@sdsc.edu)] For all those which are under the jurisdiction (=curse?) of the GEMA: the video (mp4) can also be found here.

(Free) Philosophical Transactions

The Royal Society opened their digital archives, reaching back to the very first volume –

“Giving some (account) of the present undertakings, studies, and labours of the INGENIOUS in many considerable parts of the WORLD.” I like this as a plain mission statement for a scientific journal, namely to describe what the (mad) scientists are up to. Of course, the first issues are

… very different from today’s journal, but in essence it served the same function; namely to inform the Fellows of the Society and other interested readers of the latest scientific discoveries. As such, Philosophical Transactions established the important principles of scientific priority and peer review, which have become the central foundations of scientific journals ever since.

(see http://rstl.royalsocietypublishing.org/) Just a little correction: Since the first installment of the “Journal des Sçavans” appeared a few month before the Philosophical Transactions, it’s is the second (not the first, obviously) scientific journal ever to be published in europe. While the Journal des Sçavans changed focus towards literature after the french revolution, the Philosophical Transactions now is definitely the oldest and still one of the most influential scientific journals around. (You wouldn’t find that info on the english speaking part of wikipedia, mind you).

In the now publicly available archives, there are many jewels waiting to be found – here are a few to get started (thanks for hints to heise.de) :

– Isaac Newton (1671) “New Theory of Light and Color”

– Charles Darwin (1839) “Observations on the Parallel Roads of Glen Roy, and of Other Parts of Lochaber in Scotland, with an Attempt to Prove That They Are of Marine Origin”

– James Clerk Maxwell (1865) “Dynamical Theory of the Electromagnetic Field”.

Nostalgia just isn’t what it used to be

To add to the category “yesterday’s views of tomorrow” – this “vision” from 1969 is in some aspects coming scarily close to what we call the ‘internet’ now:

Contrast this (rather narrow) “shopping/house/kids/surveillance/car/bills&taxes” outlook on the essentials of life with this view on the “computer network called ‘internet'” from 1993