A Nobel Laureate’s views on creating Meaning from Data

Image © MRC Laboratory of Molecular Biology, Cambridge, UK

Praise for the Praiseworthy

Today the recipients of the 2017 Nobel Prize for Chemistry were announced [1]. I was delighted to learn that one of the three new Laureates was Richard Henderson, former Director of the UK Medical Research Council’s Laboratory of Molecular Biology in Cambridge; an institute universally known as the LMB. Richard becomes the fifteenth Nobel Prize winner who worked at the LMB. The fourteenth was Venkatraman Ramakrishnan in 2009. Venki was joint Head of Structural Studies at the LMB, prior to becoming President of the Royal Society [2].

MRC Laboratory of Molecular Biology

I have mentioned the LMB in these pages before [3]. In my earlier article, which focussed on Data Visualisation in science, I also provided a potted history of X-ray crystallography, which included the following paragraph:

Today, X-ray crystallography is one of many tools available to the structural biologist with other approaches including Nuclear Magnetic Resonance Spectroscopy, Electron Microscopy and a range of biophysical techniques.

I have highlighted the term Electron Microscopy above and it was for his immense contributions to the field of Cryo-electron Microscopy (Cryo-EM) that Richard was awarded his Nobel Prize; more on this shortly.

First of all some disclosure. The LMB is also my wife’s alma mater, she received her PhD for work she did there between 2010 and 2014. Richard was one of two people who examined her as she defended her thesis [4]. As Venki initially interviewed her for the role, the bookends of my wife’s time at the LMB were formed by two Nobel laureates; an notable symmetry.

2017 Nobel Prize

The press release about Richard’s Nobel Prize includes the following text:

The Nobel Prize in Chemistry 2017 is awarded to Jacques Dubochet, Joachim Frank and Richard Henderson for the development of cryo-electron microscopy, which both simplifies and improves the imaging of biomolecules. This method has moved biochemistry into a new era.

[…]

Electron microscopes were long believed to only be suitable for imaging dead matter, because the powerful electron beam destroys biological material. But in 1990, Richard Henderson succeeded in using an electron microscope to generate a three-dimensional image of a protein at atomic resolution. This breakthrough proved the technology’s potential.

Electron microscopes [5] work by passing a beam of electrons through a thin film of the substance being studied. The electrons interact with the constituents of the sample and go on to form an image which captures information about these interactions (nowadays mostly on an electronic detector of some sort). Because the wavelength of electrons [6] is so much shorter than light [7], much finer detail can be obtained using electron microscopy than with light microscopy. Indeed electron microscopes can be used to “see” structures at the atomic scale. Of course it is not quite as simple as printing out the image snapped by you SmartPhone. The data obtained from electron microscopy needs to be interpreted by software; again we will come back to this point later.

Cryo-EM refers to how the sample being examined is treated prior to (and during) microscopy. Here a water-suspended sample of the substance is frozen (to put it mildly) in liquid ethane to temperatures around -183 °C and maintained at that temperature during the scanning procedure. The idea here is to protect the sample from the damaging effects of the cathode rays [8] it is subjected to during microscopy.
 
 
A Matter of Interpretation

On occasion, I write articles which are entirely scientific or mathematical in nature, but more frequently I bring observations from these fields back into my own domain, that of data, information and insight. This piece will follow the more typical course. To do this, I will rely upon a perspective that Richard Henderson wrote for the Proceedings of the National Academy of Science back in 2013 [9].

Here we come back to the interpretation of Cryo-EM data in order to form an image. In the article, Richard refers to:

[Some researchers] who simply record images, follow an established (or sometimes a novel or inventive [10]) protocol for 3D map calculation, and then boldly interpret and publish their map without any further checks or attempts to validate the result. Ten years ago, when the field was in its infancy, referees would simply have to accept the research results reported in manuscripts at face value. The researchers had recorded images, carried out iterative computer processing, and obtained a map that converged, but had no way of knowing whether it had converged to the true structure or some complete artifact. There were no validation tests, only an instinct about whether a particular map described in the publication looked right or wrong.

The title of Richard’s piece includes the phrase “Einstein from noise”. This refers to an article published in the Journal of Structural Biology in 2009 [11]. Here the authors provided pure white noise (i.e. a random set of black and white points) as the input to an Algorithm which is intended to produce EM maps and – after thousands of iterations – ended up with the following iconic mage:

Reprinted from the Journal of Structural Biology, Vol. 166. © Elsevier. Used under licence 4201981508561. Copyright Clearance Center.

Richard lists occurrences of meaning being erroneously drawn from EM data from his own experience of reviewing draft journal articles and cautions scientists to hold themselves to the highest standards in this area, laying out meticulous guidelines for how the creation of EM images should be approached, checked and rechecked.

The obvious correlation here is to areas of Data Science such as Machine Learning. Here again algorithms are applied iteratively to data sets with the objective of discerning meaning. Here too conscious or unconscious bias on behalf of the people involved can lead to the business equivalent of Einstein ex machina. It is instructive to see the level of rigour which a Nobel Laureate views as appropriate in an area such as the algorithmic processing of data. Constantly questioning your results and validating that what emerges makes sense and is defensible is just one part of what can lead to gaining a Nobel Prize [12]. The opposite approach will invariably lead to disappointment in either academia or in business.

Having introduced a strong cautionary note, I’d like to end this article with a much more positive tone by extending my warm congratulations to Richard both for his well-deserved achievement, but more importantly for his unwavering commitment to rolling back the bounds of human knowledge.
 
 
If you are interested in learning more about Cryo-Electron Microscopy, the following LMB video, which features Richard Henderson and colleagues, may be of interest:


 
Notes

 
[1]
 
The Nobel Prize in Chemistry 2017.
 
[2]
 
Both Richard and Venki remain Group Leaders at the LMB and are actively involved in new scientific research.
 
[3]
 
Data Visualisation – A Scientific Treatment.
 
[4]
 
Her thesis was passed without correction – an uncommon occurrence – and her contribution to the field was described as significant in the formal documentation.
 
[5]
 
More precisely this description applies to Transmission Electron Microscopes, which are the type of kit used in Cryo-EM.
 
[6]
 
The wave-particle duality that readers may be familiar with when speaking about light waves / photons also applies to all sub-atomic particles. Electrons have both a wave and a particle nature and so, in particular, have wavelengths.
 
[7]
 
This is still the case even if ultraviolet or more energetic light is used instead of visible light.
 
[8]
 
Cathode rays are of course just beams of electrons.
 
[9]
 
Henderson, R. (2013). Avoiding the pitfalls of single particle cryo-electron microscopy: Einstein from noise. PNAS This opens a PDF.
 
[10]
 
This is an example of Richard being very, very polite.
 
[11]
 
Shatsky, M., Hall, R.J., Brenner, S.E., Glaeser, R.M. (2009). A method for the alignment of heterogeneous macromolecules from electron microscopy. JSB This article is behind a paywall.
 
[12]
 
There are a couple of other things you need to do as well I believe.

 

From: peterjamesthomas.com, home of The Data and Analytics Dictionary