Drug Baron Blog

Latest Post

March 6, 2018 no comments

Cult of Crystallography

Biological macromolecules, such as proteins and DNA, are very small and very complex. It is something of a technological miracle, therefore, that we can visualise their three-dimensional structures at atomic resolution. The first, and still by far the dominant, method of solving these structures is crystallography.

The principal is simple: by packing many millions of molecules into a repeating crystal lattice, the diffraction pattern of X-rays passing through the crystal captures information about the structure of the individual molecules. In effect, the structural information from many identical molecules amplifies the signal to the point where it can be read and decoded.

This ability to see the structures of individual protein molecules was a huge breakthrough in biology. It may not be as famous as the DNA double helix, but the first protein structure, earned a Nobel prize for Max Perutz in 1962, the same year that Watson, Crick and Wilkins were honoured for solving the DNA structure by the same crystallographic technique.

In the intervening six decades, many thousands of protein structures have been solved in this way, and delivered mechanistic insight into the many functions of proteins, as structural components, molecular motors, enzymes, synthetic factories and signalling networks. They have underpinned the development of numerous drugs, designed to bind in highly specific ways to particular proteins. Today, variations on a theme even allow us to visualise structures of membrane-bound proteins that traditionally eluded crystallisation.

So great has been the positive impact of having a window on these ultra-microscopic structures that its hard to imagine that the ubiquitous application of crystallography has had a unintended negative consequence for our understanding of biology.

Structures obtained using these methods that average across millions of molecules are so embedded in our thinking that we accept them as representative of the protein in vivo, almost without thinking, and certainly without constantly bearing in mind the single biggest assumption of crystallography: that all the molecules are the same.

Together with the cult of DNA centricity, this cult of crystallography has led to a very distorted view of what we think of as a protein. When we name a protein, such as apolipoprotein E (one of DrugBaron’s favorite proteins), the implicit assumption is that we refer to a homogeneous population of molecules, all with the same primary sequence (that is, the same amino acid building blocks in the same order, exactly as encoded by the DNA sequence of the apoE gene) and all with the same three-dimensional structure and conformation …

October 2, 2013 no comments

PheWAS – the tool that’s revolutionizing drug development that you’ve likely never heard of

Late-stage attrition kills returns on pharma R&D investment.  One way to reduce attrition is to...

August 8, 2012 2 responses

“Idea Bubbles”: The dangers of big theories in low-validity environments

This week, Pfizer and J&J finally discontinued development of iv bapineuzumab for Alzheimer’s Disease (AD)...

June 4, 2015 no comments

A DrugBaron Glossary

To mark the fifth anniversary of this blog, as well as the launch of the...

May 20, 2015 comments

The perils of ignoring negative data

This week, Eleven Biotherapeutics ($EBIO) announced the failure of its Phase 3 trial of an...

May 15, 2015 no comments

What the travails of the UK’s largest grocer can teach the pharmaceutical industry

In the five years since DrugBaron posted his first article, entitled “Hard Times, Harder Times”,...


Yearly Archive