July 13, 2024

I, Science

The science magazine of Imperial College

The Nobel Prize in Chemistry 2017 was awarded to Jacques Dubochet, Joachim Frank and Richard Henderson for developing cryo-EM for the high-resolution structure determination of biomolecules in solution.

The 2017 Nobel Prize for Chemistry

This article belongs to a series on the 2017 Nobel Prizes

The first line of Jacques Dubochet’s CV reads: ‘1941 — conceived by optimistic parents’. Delusion, rather than optimism, would have been required to predict how Jacques would irreversibly change the world of biochemistry.

On Wednesday the Nobel Committee revealed the names of three more scientists who would join the ranks of Ernest Rutherford, Marie Curie, and Linus Pauling, as Nobel Laureates of Chemistry. Enter: Professor Jaques Dubochet, Doctor Joachim Frank, and Doctor Richard Henderson.

Cryo-electron microscopy: Caught in the act

It’s not just for artists that a picture can paint a thousand words. For scientists, the significance of an image is not to be underestimated, be it for increasing public understanding or for developing new hypotheses, and this year’s Nobel Prize for Chemistry is a testament to that.

There is a problem that lies at the heart of all imaging in biochemistry. In order to be able to visualise the contents of a cell, as a whole or just its individual components, you need to alter the environment that the cell is sitting in.

Commonly, this means purifying a specific component of the cell — like a protein you’re interested in — and analysing it using X-rays. Techniques like these, which use X-rays, also require a special preparation technique called crystalisation — a specific way of preparing the sample so that it is ultra-pure. Other techniques require the use of chemicals to fix the whole cell to a microscope slide, killing it in the process.

Using these crude methods to visualise what’s going on in side a cell is like a school inspection day: the mere act of using these techniques alters what you see. You can’t be sure the children are this well behaved all of the time…

Cryo-electron microscopy (Cryo-EM) allows biochemists to be undercover agents, to watch what’s happening in the cell with close to full confidence that they’re seeing the real picture. Using a technique called vitrification, Cryo-EM rapidly freezes a cell sample, allowing us to look at what the cell gets up to when it’s not on its ‘best behaviour’.

In nailing down this technique during the 70s, Dubochet laid the groundwork for what would become a Nobel prize-winning collaboration.

‘The sun comes back’: Exposing the shadow of structural biology

The next line of Jacques Dubochet’s unorthodox CV reads: ‘1946 — no longer scared of the dark, because the sun comes back; it was Copernicus who explained this’.

For years until the development of Cryo-EM, the most detailed imaging techniques required crystalisation. Vital proteins on the outer surface of a cell known as membrane proteins are very difficult to accurately visualise through crystallisation, and so this black hole in our knowledge of protein structures still existed. Progress in imaging techniques had been made, but the momentum was fragile. Things had started to go dark; as Dubochet would say — the sun needed to come back.

Around the same time as Dubochet was perfecting his vitrification technique, a fresh-faced German post-doc had just arrived in Albany, NY, for his new job at the Wandsworth Centre. Joachim Frank was working on a way of reconstructing multiple 2D images from an electron microscope into a three-dimensional picture. Frank was able to perfect the technique that would become known as single-particle reconstruction — a vital piece to the puzzle of Cryo-EM.

It might strike you as strange, that two key discoveries from the 70s only resulted in a Nobel Prize 40 years later, but there was another key ingredient that was missing: stubborn scientific persistence.

‘Realising the potential’: the missing ingredient of Cryo-EM

The final character in this story is Dr Richard Henderson. For most of his career, Henderson didn’t seem all that interested in studying electron microscopy itself. Most of Henderson’s work had been on the structure of proteins in bacteria, and he’d had a lot of success. Part of this success was due to the level of detail in Henderson’s images – but these images were from the standard crystallographic methods. Henderson knew that he could do better.

In an article in 1995, Realising the potential of electron cryo-microscopy, Henderson proposed that the work done by people like Dubochet and Frank on this new technique of Cryo-EM had laid foundations for it to surpass the current resolution crystallographic methods are able to give us, allowing us to gain insight into cell structure in ways we had never dreamed possible.

Over the next twenty years Dubochet, Frank and Henderson, along with a number of talented scientists, would continue to work diligently on trying to make Cryo-EM the technology it is today. As the winner of the Nobel Prize for Chemistry in 2009, Venki Ramakrishnan, said: this work showed “the value of patiently supporting basic science.”

In an interview in 2009 Ramakrishanan also told reporters that “science is collaborative — it shouldn’t be a competition.” The story of Dubochet, Frank and Henderson shows young scientists what can be achieved when you heed Venki’s advice.

But it wasn’t just collaboration that made this giant leap forwardn possible. Like three parents, Dubochet, Frank and Henderson gave a piece of themselves to the cause of Cryo-EM. You might say it was an idea, ‘conceived by optimistic parents.’

Stefan Rollnick is studying for an MSc in Science Communication at Imperial College London

Banner Image: Improving resolution by cryo-EM, NIH Image Gallery