Revealing the Secret World Inside the Cell

There is a secret world inside our cells, akin to the fascinating wonderland that Alice discovered. Instead of falling down a rabbit hole, scientists explore this incredible realm using various tools, such as the microscope, which serve as windows to the intricate details of cellular processes occurring within fractions of a second. Physicists have played a crucial role in enabling the observation of these dynamic processes by developing diverse tools. During two #LINO24 Agora Talks, we were fortunate to have Laureates who explained how they came to these techniques.

The Secret World

On #LINO24 Monday the Nobel Laureate Stefan W. Hell who shared the Nobel Prize in Chemistry in 2014 with Eric Betzig & William E. Moerner for “The Development of Super-Resolved Fluorescence Microscopy”, entered the stage in the main hall, to share his insights in his part of the Agora Talk, entitled “Single Molecule Methods and a Physics Understanding of Biology | MINFLUX: A New Physical Principle To Resolve Position and Movements of (Bio)Molecules Down to Angströms”.

Hell successfully overcame the limitations of traditional microscopes by utilizing fluorescence. With the innovative method pioneered by Hell in 1994, it became feasible to capture pictures that facilitate the tracking of internal cellular processes, revealing the secret world inside the cell.

He began with a simple and good question: “How to localize a fluorescent emitter with maximum accuracy, precision, and speed?” Throughout the Agora Talk, he discussed the workings of the traditional microscope and the inherent challenges of achieving highly precise and accurate results. He then delved into MINFLUX, which allows tracking target objects within a cell with an impressive 1-3 nm resolution in three dimensions.

This technique can capture protein movements with remarkable temporal and spatial precision of up to 1.7 nanometers per millisecond. Hell explained how his team utilized it to study the stepping mechanism of the motor protein kinesin-1 on microtubules. Furthermore, he outlined their studies which unveiled two distinct movements, Chasse-Inchworm and Hand-over-Hand, and showcased their investigation of other proteins like Dynein. Finally, measuring the distance within molecules with extreme accuracy was also on the agenda of Stefan Hell.

Step by Step

Steven Chu delivered the second part of the Lindau Agora Talk titled “Single Molecule Methods and a Physics Understanding of Biology.” Chu shared the Nobel Prize in Physics in 1997 with Claude Cohen-Tannoudji and William D. Phillips for the “development of methods to cool and trap atoms with laser light.” In the 1980s, he worked on the development of a technique for slowing down and cooling atoms and molecules moving at high speeds at room temperature. By utilizing light particles with specific energies, and photons they could impact the motion of the particles.

Chu’s research involved meticulously tracking the movements of proteins such as Dynein and Kinesin step by step. This process was highly complicated and challenging. To emphasize the importance of careful observation and tracking, he quoted the famous baseball player Yogi Berra, who once said: “You can observe a lot just by watching.” This is what Chu and his team accomplished.

He then proceeded to explain their experiments aimed at tracking single molecular steps at different temperatures, focusing on the timings between these steps. Chu emphasized the significance of even minor differences, stating, “The variance between 5.0 and 5.2 is notable in biology.” Highlighting various types of Dynein movements, he clarified that each movement has a specific time duration. He stressed the importance of careful consideration when making these measurements and thinking about it.  “You always have to say what you measure is not only what you see but also what you could measure you have to think about”, said Chu.

Galaxies Inside the Cell

A few days later during the Lindau Meeting week, William E. Moerner took the same stage in the main hall, a Nobel Laureate who shared the Nobel Prize in Chemistry in 2014 with Stefan W. Hell. The Agora Talk was entitled “Adventures With Single Molecules and SARS-CoV-2”. 

He commenced by reflecting on memories from his childhood, where he was fortunate to have two supportive and encouraging parents. His father had studied physics and chemistry and was a professional photographer, who played a significant role in shaping W.E.’s understanding of chemistry and light from an early age. His mother, an English teacher, dedicated time to reading with him, which greatly contributed to his proficiency in English language skills. “In the first 5 years, read to the child, talk to the child. Even if the child is still too young to speak,” said Moerner.

The launch of the Sputnik-1 satellite by the Russians in 1957 prompted a shift towards mathematics and science in the United States, creating favorable conditions for Moerner to pursue a career in science. This led to an increased emphasis on chemical experiments, studies of physics and mathematics, and advancements in laser technology.

Moerner discussed the advancements made by scientists in tracking single molecules, highlighting how it was once considered as an unattainable dream with the near impossibility of imaging those molecules with high precision. Many believed that “single molecules cannot be detected” even Erwin Schrödinger. “When experts say ‘It cannot be done,’ this is an important signal: you should double down,” said Moerner. “You just might solve the problem and make a great discovery,” he added.

He explained the mechanism of super-resolution and presented images illustrating the movement of individual particles, reminiscent of shimmering stars in the night sky or enchanting galaxies. Those who view these striking images would be amazed by their existence within our cells.

Then Moerner discussed the application of super-resolution in SARS-CoV-2, the virus responsible for the COVID-19 pandemic, revealing highly detailed images of the viral RNA and various proteins present in infected cells. He delved into the intricacies of the viral genome, the transmission of viral infections within human cells, and the processes involved in converting genetic material into proteins. 

The power and precision of super-resolution were evident as it unveiled the infection’s details and generated images just 24 hours post-infection, resembling a galaxy surrounded by viral RNA particles.

Altogether, without the unwavering determination of scientists to overcome the obstacles they faced, none of this progress would have been revealed. “We have no choice but to use science to solve big problems,” said Moerner.