Saturday, October 01, 2011

The Dynamic Personality of Dorothee Kern

This post was written for Ada Lovelace Day – an international day of blogging to celebrate the achievements of women in technology and science.

Dorothee Kern often starts her biochemistry talks and lectures with a movie of a basketball game. Not what you'd expect perhaps, but then how many science professors used to captain an international basketball team? Kern's research focuses on protein dynamics, an area of active research worldwide (and indeed the subject of my own PhD project). When I started delving into the literature, her name came up again and again, one Science or Nature paper after another from her lab at Brandeis University.

Protein structure - the way a chain of amino acid subunits folds on itself to form the three-dimensional structure of the active protein - is a much-studied problem. And as proteins perform such a vast variety of roles in the cell, and represent therapeutic targets for many drugs, understanding these structures is essential. X-ray crystallography is the method of choice. We trap proteins in crystal 'cells' and fire X-rays at them, and the resulting diffraction pattern - the way in which the X-rays are scattered by the protein atoms - allows us to deduce the relative geometric positions of the atoms, giving the structure. In the early days, when Dorothy Hodgkin was solving the Nobel-prize winning structure of insulin, and Rosalind Franklin was producing her famous DNA structures, the process involved complex mathematical calculations and constructing elaborate physical models by hand. Fortunately now, with the help of computational methods, the process has been speeded up to the point where solutions can be churned out with relative ease, and tens of thousands of structures are available in the online Protein Data Bank. So much structural data is available that it looks as though the problem is solved.

But it is not so. In fact the dependence on crystal structures for our understanding of proteins could be seen as having distorted our view of what they are and how they work. Traditionally proteins are considered to be fairly static structures, except when a particular action is required to perform a certain function. But in fact they are in constant motion - if we could look close enough to see their motions, we'd see the vibrations of individual atoms and bonds, functional groups moving as coherent units: sometimes we'd see the two halves of the protein opening and closing like a seashell, like a breathing living thing. A protein does not have just one structure, but many, constantly shifting from one to another. To understand protein function, we need to consider not just structure, but dynamics.

This is one of the big paradigm shifts in protein science, pioneered by Kern in a seminal paper, The Dynamic Personalities of Proteins. Here she challenges the traditional 'static' view of proteins, proposing instead the use of energy landscape models more usually associated with the protein folding process, and makes a bold attempt to bridge biology and physics in a unified view of proteins from atomic structure to biological function. She and her research group used a variety of experimental and computational methods to determine the dynamics of a model protein on various timescales, discovering previously unknown states that occur with low probability but are vital to the overall function. And the results also showed that the seemingly random, miniscule, fast movements of individual atoms in fact contribute to the slower, large-scale motions of the whole molecule - the organisation is hierarchical, multi-scale in both time and space. As Kern explains in a characteristic basketball analogy: each individual player in the team is continuously moving, 'with or without the ball', each contributing in their own small way to the concerted actions and achievements of the team.

My own research uses mathematics to model and predict the multiscale dynamics of cell-cycle proteins involved in cancer and other diseases, with a view to being able to develop inhibitors to interfere with protein function in a predictable way. It was easy at first to take the dynamic model of proteins for granted; it had already become such a well-established part of modern protein science. But like so many great ideas in science, although it looks simple with hindsight, it took an imaginative, unconvential thinker to realise it and to challenge existing orthodoxy.

Kern is a believer in pursuing interests outside science - energising, creative ones; her colleagues describe her as the most energetic scientist they know. It's easy to forget sometimes, especially when it comes to biology, that science is as much about creativity and abstract thinking, as about churning out results. That's why, this Ada Lovelace Day, I wanted to talk about Dorothee Kern.