What is the Cryogenian Period?

The cryo-electron microscope uses electron beams to image frozen biomolecules to obtain the three-dimensional structure of the molecules.

The cryo-electron microscope uses electron beams to image frozen biomolecules to obtain the three-dimensional structure of the molecules.

At present, cryo-electron microscopy is very sensitive, and a shout will bring great errors and cause the experiment to fail.

One of the most advanced cryogenic electron microscopes in the world: located in the UK Medical Research Council Laboratory of Molecular Biology (LMB), the US $ 7.7 million, bulky, is a metal box about 3 meters high through Orange cables that connect cells can transmit trillions of bytes of data. ^[1]

One of these people is Rod MacKinnon, a biophysicist at Rockefeller University. He won the Nobel Prize in 2003 for analyzing the crystal structure of some ion channels. MacKinnon is now obsessed with cryo-electron microscopy. "I'm on the slope of the learning curve now and I'm very eager." MacKinnon said. He plans to use cryo-electron microscopy to study how ion channels are turned on and off.

In 1997, Henderson declared very firmly that cryo-electron microscopy would become the mainstream tool for protein structure analysis. Today, almost 20 years later, his predictions have more confidence than he did then. Henderson said that if cryogenic electron microscopy continues to develop and the technical problems are resolved, cryogenic electron microscopy will not only become the first choice to analyze protein structure, but the mainstream choice. This goal is not far from us.

Structural biologist Sjors Scheres said that more cryogenic electron microscopes are needed in the future and that it will become the mainstream of structural biology in the future.

At the end of 2013, Nature Methods magazine awarded the technology of the year to single-cell sequencing. At the same time, the magazine also introduced the technologies worthy of attention in 2014, including single-particle low-temperature electron microscopes.

Two articles published in 2013 introduced researchers at the University of California, San Francisco using a newly developed single-electron counting detector, demonstrating that electron-beam-induced movement significantly reduces resolution, and they found that fast reading In combination with an almost noiseless electronic count, the image blur is corrected and the image information is restored to a high resolution. ^[2]

Milestones in structural biology appeared in 2015, and the era of cryo-electron microscopy technology came.

Cryogenic electron microscopy shocked structural biology. Over the past 30 years, cryo-electron microscopy has revealed the fine structures of ribosomes, membrane proteins, and other key cellular proteins. These findings were published in top magazines. Structural biologists say it's no exaggeration to say that cryo-electron microscopy is undergoing a revolution: cryo-electron microscopy can quickly generate high-resolution molecular models, far exceeding methods such as X-ray crystal diffraction. Laboratories that relied on old methods to win Nobel prizes are also working hard to learn the technology. This new model can accurately reveal the necessary mechanisms for cell operation and how to target disease-related proteins.

"Cryogenic electron microscopy can solve many previously unsolvable puzzles," said David Agard, a structural biologist at the University of California in San Francisco.

When Scheres was recruited into LMB, his mission was to help improve the cryo-electron microscope, and he succeeded. In August 2015, they published one of the most exciting achievements in this field: high-resolution pictures of Alzheimer's-related enzymes, which include about 1200 amino acids of the enzyme with a resolution of a few tenths of a nanometer.

Biologists are still working hard to develop the technology with a view to using it to solve the fine structure of small or deformable molecules-a challenge for cryo-electron microscopy. Eva Nogales, a structural biologist from the University of California, says that whether it is called a revolution or a leap, low-temperature electron microscopy does open the door. ^[3]