Cambridge’s Latest Nobel Prize

Cambridge’s Latest Nobel Prize

Max Wilkinson explores the science behind this year’s Nobel Prize in Chemistry

At the core of all life on earth is chemistry: from the way DNA is built and read to the way the proteins it encodes make a cell tick. The best way to truly understand this chemistry is to directly visualise the atoms of life. This is commonly achieved by X-ray crystallography, where biomolecules are purified and forced into a regular crystal lattice before analysis by X-ray diffraction. The technique shows life in incredible detail, revealing for example the DNA double helix and the spinning turbines that generate a cell’s power, but it requires purification of large amounts of the biomolecule in a pure, rigid form. Many essential biomolecular complexes like the DNA replication machinery, ribosomes, splicing machinery and motors tend to be very large, dynamic, and difficult to purify, so defy crystallisation. Therefore, until recently many essential processes of life had never been seen at the detail needed to understand their chemistry.

This year’s Nobel Prize in Chemistry acknowledges breakthroughs in a technique that now overcomes many limitations of X-ray crystallography: cryo-electron microscopy (cryo-EM). In cryo-EM, a preparation of biomolecules is rapidly frozen and then imaged in an electron microscope. Different 2D views of the biomolecule are then computationally aligned in 3D to provide a molecular structure. Because molecules are imaged individually only small amounts of material are required, the biomolecules can be very flexible, and large molecule size is in fact an advantage. Molecules recalcitrant to X-ray crystallography are suddenly made visible by cryo-EM.

The prize winners, Richard Henderson, Jacques Dubochet, and Joachim Frank, each made seminal contributions in the development of cryo-EM.  Jacques Dubochet, working at EMBL, discovered how to freeze biomolecules without the solvent water forming ice crystals. Joachim Frank at Columbia University, New York developed some of the first methods and software for 3D reconstruction of the biomolecule from the 2D images taken in the microscope. Richard Henderson, working at the Medical Research Council Laboratory of Molecular Biology (MRC LMB) in Cambridge, worked out how to visualise the biomolecules without the electron beam of the microscope destroying the sample. Richard Henderson also made crucial theoretical advances in proving the ability of cryo-EM to extract high resolution information, and was the first to use cryo-EM to solve an atomic resolution biomolecular structure. After announcement of the Nobel, Richard Henderson said:

“I am delighted for everybody in the field that the Nobel Prize for Chemistry has been awarded to acknowledge the success of cryo-EM.  I am particularly pleased that Jacques Dubochet has been recognised as the key person who kick-started the field with his method of rapid-freezing in the early 1980s, a crucial advance.”

The developments of the laureates, combined with other technical advances in microscope quality and the detectors used to take images (to which Richard Henderson has also made important contributions), have been transformative for structural biology. Biomolecules that defied X-ray crystallography for decades have suddenly become visible, and almost every issue of Cell, Nature, and Science since 2014 has some new cryo-EM portrait of an important biological process. This year’s Nobel continues a long tradition of acknowledging structural biology breakthroughs in Cambridge: from Nobel Prizes to Watson and Crick for the first DNA structure (1962), to Kendrew and Perutz for the first X-ray crystallography structures of proteins (1962), to Klug for the first EM reconstruction of a biomolecule (1982), and to Walker and Ramakrishnan for iconic crystal structures (1997 and 2009).  The MRC LMB now has over 100 scientists who have come to Cambridge to learn cryo-EM, and the technique is spreading rapidly over the world. At a press conference after the prize was announced, Richard Henderson predicted that one day, cryo-EM will make solving a biomolecular structure as easy as sending a sample in an envelope to a facility, and getting the structure back the next day. This, combined with ongoing work in direct atomic resolution imaging of cells by cryo-EM, means we are set for a revolution in the detail with which we understand life’s mechanisms.

Image credit: eLife – the journal. Image was modified by cropping and taking a screenshot of the original image.