just stood up. It's a microscopic universe within each cell. This is an unprecedented

view of the cellular world, where we can actually see immune cells scooping up sugars in the

ear of a zebrafish in real time. Focusing only on the crawling immune cells, we've noticed

two classes of them. One, it seems was not hungry at all, but it was very active in terms

of trying to figure out what the environment is. But there was another one that was slouching

around with a lot of food in its belly. We can actually conceptualize, visualize, and

analyze the contents of each of these cellular compartments in this crawling immune cell

as it's scooping up its environment. That is a level of detail no one's ever seen before.

We’re living in a new era of cell biology, where microscopy advancements are

giving biologists the opportunity to reveal the hidden patterns of cells. What we expect

to learn from here on out will transform our understanding of human health and rewrite

the textbooks on the fundamental unit of life.

For centuries, microscopes have illuminated

previously invisible worlds. We’ve learned how cells divide and even discovered the existence

of bacteria and microorganisms. These historical breakthroughs are often found in your typical

high school textbook. I fell in love with the cell and wanting to understand the cell

when I saw textbook images. I learned as I started studying the cell, that those are

vast simplifications of what those structures actually do and what's inside the cell. They

don't allow us to embrace the messiness and complexity in the cell. At research organizations like

the Allen Institute for Cell Science, biologists are taking a more integrated view to better

understand this complexity. So we at the Institute are trying to think of all the structures

of the cells in a holistic manner. If we don't understand which parts of the cell interact

with which other ones we won't ever be able to understand the true mode of action of a

drug, or perhaps where the side effects come from. It's that integrated knowledge of how

when you pull here, you move there, that allows us to understand the cell or the tissue or

the organism properly. And if you don't do that you're going to miss really important things.

In order to see the patterns that are actually happening in the cell in space

and time, we have to be able to image the cell well in space and time. New microscopy

is what's allowing us to image a cell in three dimensions, in their native context without

killing and hurting the cells, which is just absolutely needed

for us to just study the cell as it is. But seeing biological processes inside living

samples without harming them is easier said than done. One of the ways scientists image

these dynamics is with fluorescence microscopy. However, harsh light from this technique can

cause phototoxicity, meaning the cell can get sick during the imaging session. Lattice

light-sheet microscopy was invented a few years ago to correct for that challenge.

So it's a non-diffracting beam, meaning that as the beam is traversing through the sample,

it's not converging or diverging. We put several of these at very specific positions

such that you interfere every beam with itself and then create a very thin sheet of light.

This fine sheet of light repeatedly sweeps over a sample in order to avoid the damage

that’s typically associated with other microscopy techniques. The result builds a high resolution

3D movie depicting relatively undisturbed living cells functioning over time.

But tissues and other biological structures surrounding cells tend to scramble the light from the

microscope, resulting in blurriness. To compensate for this, the same team behind the lattice

light-sheet microscope borrowed a trick astronomers use to get clear views of distant stars - adaptive optics.

Just like how astronomers use lasers as “guide stars” to course correct blurriness

in telescopes, the process for looking at the infinitesimally small world of cells through

thick tissues and in living samples works in the same way. Using a laser guide, aberrations

that distort the light’s path are revealed and corrected by the microscope. There's

several examples where we've worked with some of the biologists, and showed them a few of

our samples. Their reactions have typically been, "Even though I've been studying this

for a decade, it's as if I'm looking at this for the first time." And that is always inspiring.

Even just talking about this is giving me goosebumps.

With such promising feedback from

biologists, Gokul and his team of instrumentation scientists and computational

experts are taking that technology one step further in a newly created imaging center

in Berkeley. This is unlike any microscope you may have seen in high school. Its purpose

is to shed light on molecular mechanisms that are either poorly understood or not understood

at all. MOSAIC is the Swiss army knife microscope, as we have called it during development. And

the reason we've called it the Swiss army knife is because when we were trying to miniaturize

the adaptive optics with lattice light sheet, we realized that all of the components that

go into building that microscope can be repurposed to build a completely different microscope.

MOSAIC combines about seven to 10 different imaging modalities into one microscope. You

can reconfigure or transform the microscope from one mode into another mode. Such that

you can interrogate your sample using different modalities.

We've imaged everything from live imaging, also everything that's dead as well.

Cells didn't evolve in isolation. Cells didn't evolve on a cover slip. The goal of this whole

project was to see, hey, can we create a tool that will allow biologists to be able to look

at their particular processes in a more physiological, more natural environment.

For you to have an effect in medicine and other fields, you need to understand to be able to perturb,

mitigate and or intervene, right?  And that's basically what this is doing. This instrument

is going to be laying the groundwork in order to help understand

how a virus enters a cell. For instance, if you can understand

the mechanism by which it's fusing to the plasma membrane and then injecting

its contents into the cell, you now have the ability to intervene.

The team behind MOSAIC

has already built one instrument, and is in the process of bringing a second one online.

The next step will be opening up the instrument to biologists. Because the thing is we can

only get so far by ourselves. The goal is to make sure folks that have the ability to

have the impact, we want to make sure we break the barriers down. Whether it's access to

instrument time, whether it's access to computational resources or working with the computational biologists.

With tools like these soon coming online, biologists like Susanne are excited

about the next decade of cell biology. We basically have a little alien world that none

of us can wrap our minds around, and it's all of these technologies that are allowing

us to start to do that more intuitively. Imagine a world where you could look at a cell and

you know what it's doing, what it has done and what it will do. That means that you could

collect a pathological specimen, and without too much perturbation or staining collect

a whole bunch of information and features just from the image, that let a pathologist

know something about the prognosis of the disease and the mechanism of why that's the case.

There will of course be more and more innovation. That's always how it works, but

this set of innovation is going to get translated into useful results for everyone.

There's literally trillions of inanimate molecules inside of cells that work together somehow

to create life. That's basically what thousands of scientists around the world are trying

to understand is how life works. We want to watch the dynamics, the interplay between

these molecules in order to really understand the complexity, understand the beauty of what

is happening within the cells. Biology is probably one of the last human forefronts. It's

the age of exploration again, but instead of looking out at the galaxies, we're looking

at the galaxies inside of the cells.