Science

Up close and cold: Cryo-electron microscopy takes the 2017 Chemistry Nobel Prize

This year's Nobel Prize in Chemistry honors a process that allows researchers to study the 3-D structures of vital proteins in living organisms. It's leading to new drugs. But it's shocking… and cold.

Nobelpreis Chemie Grafiken (The Royal Swedish Academy of Sciences/Martin Högbom)

The Nobel Prize committee's Goran Hansson let the words "cool method" roll off his tongue, and then let them hang in the air on Wednesday. And then with a light smile he continued to describe the achievements of the three newly-minted Nobel Chemistry laureates.

"A revolution in biochemistry," is how Sara Snogerup Linse, another member of the Nobel committee, put it moments later.

And with it three chemists — the Swiss Jacques Dubochet, the German-born US citizen Joachim Frank, and the Scottish-born Richard Henderson — were awarded the prestigious prize for developing cryo-electron microscopy.

Cryo-electron microscopy is cool for two reasons. First, the method only works at very low temperatures of more than minus 150 degrees Celsius (minus 238 degrees Fahrenheit). And second, it's enthralled scientists around the world, because it is allowing them to study vital proteins with a precision that was impossible until recently.

The technique has "opened up a completely new world to us," said Peter Brzezinski, a professor of biochemistry and member of the Nobel Prize committee. "[We're] able to see all these molecules inside the cell and how they interact." It's also become extremely helpful in the development of new medication, he said, or when studying pathogens, like the Zika virus.

Redux revolution

"I was fully overwhelmed," said Joachim Frank via telephone when journalists at Wednesday's press conference asked how he had received the news. "I thought the chances of becoming a Nobel Prize laureate were minuscule, because there are so many other innovations and discoveries that happen almost every day."

USA Chemie-Nobelpreis Joachim Frank (picture alliance/dpa/AP/R. Drew)

Joachim Frank, one of the three 2017 Nobel Prize winners for Chemistry

But Frank, Henderson and Dubochet did get the Nobel Prize. And the method is not even that new. In fact, the first prototype of an electron microscope was developed by the German Ernst Ruska in 1931. And about 50 years later, in 1986, Ruska got the Nobel Prize for Physics for "his fundamental work in electron optics."

But as good as it was, it had its limitations. So many researchers, including this year's Nobel laureates, started tinkering to make improvements.

"It wasn't the biggest surprise that this got the Nobel Prize," Holger Stark, director of the Max Planck Institute for biophysical chemistry in Göttingen, told DW. "Cryo-electron microscopy has had such a huge impact in the past few years."

Stark uses the method to study molecular machines in the human body, such as ribosomes, which produce proteins in cells. 

In the early days, cryo-electron microscopy got a bit of flak. "It was derided, because the resolution was so bad," said Stark.

But that's changed dramatically, Stark adds. And researchers who know how to use the method are in high demand. "Cryo-electron microscopy is booming."

Nobelpreis Chemie Grafiken (The Royal Swedish Academy of Sciences/Johan Jarnestad)

Cryo-electron microscopy allows researchers to analyze protein structures in incredible detail

Stark says he gets regular requests, asking whether he has any staff he could either lend or let go. "We should actually be negotiating transfer fees like in football," said with a laugh.

Like a dragonfly set in amber

For many years, scientists used X-ray crystallography to study proteins. To do that they would shoot a protein crystal with X-radiation, and then calculate its structure based on the results. This was how, for instance, the Israeli scientist Ada Yonath studied ribosomes. She was awarded the Nobel Prize for Chemistry in 2009 — only the fourth woman to receive the honor.

But there is a problem: not all proteins crystalize. So, until recently, it was impossible to study their structure. Using an electron microscope is just as little use as that method tends to destroy the proteins.

But Dubochet, Frank, and Henderson were on the case. They got to work — separate from each other — on finding a solution.

The idea was to freeze a watery protein solution — but to do it so fast that ice crystals were unable to form, because ice crystals would hinder any measurements.

"The protein is set like a dragonfly in amber," explained Stefan Raunser, a biochemist at the Max Planck Institute for Molecular Physiology, in an interview with DW.

Schweiz Chemie-Nobelpreis -Jacques Dubochet (picture-alliance/dpa/Jean-Christophe Bott/Keystone)

Jacques Dubochet developed the method of shock freezing protein solutions

The specimen can then be studied for three days at ultra cold temperatures in the cryo-electron microscope. The measurement data allows researchers to reconstruct a 3-D structure of the protein. Individual structures can even be merged like the frames of a film — so it's possible to observe the protein in action.

"We're able to learn about proteins in their smallest detail," said Raunser. He uses cryo-electron microscopy to study muscle proteins and to understand how congenital heart defects happen.

But the method is not cheap. A single machine costs about 5 million euros ($5.8 million).

"It's not the kind of money you have stuffed down the back of a sofa," said Stark.

And the upkeep of these machines is equally expensive: maintenance costs about 150,000 and 200,000 euros per year: "You need high end climate control."

The results, however, seem to make it a worthwhile investment. "If all you manage is to improve a single medication, it's paid its way," said Raunser.

From Alzheimer's to Zika

"The practical use is immense," said Nobel Prize winner Joachim Frank during Wednesday's press conference in Stockholm. "Medicine is no longer looking at organs. It looks at the processes inside the cell."

And if you understand these processes, you can improve drugs or even develop new ones.

Last year, a team led by Michael Rossmann at Purdue University in Indiana, USA, used cryo-electron microscopy to determine a high resolution structure of the Zika virus. It only took a few months, said Brzezinski, professor of biochemistry and member of the Nobel Prize committee.

"The structure shows the atomic details of the surface, which is important when developing drugs against the virus," he said.

And in September, a German-Dutch research team reported they had used cryo-electro microscopy to decode the structure of an amyloid fibril. That's the plaque that builds in the brain and is thought to be responsible for Alzheimer's disease.

Raunser says there is hope that the method will also help researchers find new antibiotics to fight drug resistance. He's been using cyro-electron microscopy for 16 years and remains excited about its potential.

"We have our machine running 24 hours a day, 7 days a week."

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