State of the Art Microscopy
complexity analogy, past, present.
The average size of a human cell is ~1 million times smaller than the average human (around ~10 micrometers). In that cell, there are ~10 billion proteins bouncing around at any given point in time. That's roughly the same number of people on planet Earth. Just like people, proteins interact with each other, form teams, work together, localize to different regions of the cell, coordinate movement over time, etc. So here's the punchline.
The complexity of interactions inside a single human cell is the same order of magnitude as the totality of human interactions on Earth at any given time.
It's crazy. Now, if I extend the analogy to microscopes and experimental interventions, it would go like this: Imagine you lived on a distant planet and you had to figure out how humans on Earth organize. You have a giant telescope, and you can see what humans are doing during the day when they are outside, but you can't really see what happens if they are covered by clouds or inside buildings. Live-cell microscopy techniques deal with the same issues in extremely creative ways. On the nanometer scale, visible light reaches its physical limits. It hazes up the imagery. The only way we can see it is if we label individual classes of proteins in a way that they emit light. Then we have to use special software to discern them from one and another.
In our analogy, let’s say it's not really practical for you to travel all the way to Earth and learn their language, but you can vaguely control what random groups of people do. Maybe you start a war between Russia and the US. Maybe you thought it would be funny to put Trump in office. Maybe you even throw an asteroid at the planet and wipe out the dinosaurs. After a long history of experiments, you were able to uncover a lot about Earth, but it is still Day One in your exploration. Here's a brief history of where we've come.
Brief history of microscopy
13th Century: Eyeglasses were widespread
1610: Galileo Galilei was one of the first recorded practitioners of telescopes for astronomy
1670: Antonie van Leeuwenhoek pioneered the use of microscopes for biology
1930: The first electron microscope
1986: The first atomic force microscope
1978: The first confocal laser scanning microscope
1992: Fluorescent green proteins were discovered (fluorescence microscopy)
2008: A Nobel prize was awarded for the discovery of glowing proteins (GFPs) ushering the age of fluorescence microscopy
Present Day (State of the Art): Real-time cellular 2D/limited 3D resolution of live/modified cells
Future (The Holy Grail): Real-time sub-cellular (nanometer) 3D resolution of a live cell (and all its protein-interactions)
Present Day
Today, we can get some crazy imagery of live cells through 3 key technological advancements that are concurrently advancing.
fluorescent protein engineering (synthetic biology advancements with CRISPR)
computer vision software (lateral application of the same tech used in autonomous driving)
highly precise manipulation of light (lasers)
We are at a very unique convergence of this 3-pronged stack that will mature quickly over the next 10 years. Innovation in this space is costly, but commoditizing this stack will unlock huge bottlenecks in basic and clinical research. Some of the most state of the art microscopy techniques produce some alien-like imagery. Here are a few cool ones. Hope you enjoy, and have an amazing rest of your day!
Clathrin-mediated endocytosis in vivo
Actin proteins appearing inside cargo proteins
Live-cell protein-level interaction imagery
Best,
Vihar Desu
Very interesting article and style Vihar. Enjoyed the read and you do a great job explaining this complex concept. Interested to see how this connects to drug discovery and development. Looking forward to more posts!!