The life unfolding inside your cells, revealed in 3D

Trying to understand life
without clearly watching it in action

is like an alien species trying
to understand the rules of a football game

from just a few snapshots.

We can learn a lot from these images.

For example, there's players
on and off the field.

There's a band.

There's even cheerleaders

having a great time watching the game.

And of course, despite learning
all of this information

from watching these pictures,

we still cannot piece together
the rules of the game.

In order to be able to do that,

we need to actually
watch the game in action.

Much of what we know about how life works

comes from watching these snapshots.

Scientists have been able to figure out
a lot by looking at similar snapshots,

but ultimately for them
to understand how life works

they need to actually watch it in action.

And this is essentially where life happens

is trying to understand

how the fundamental unit of life works,

and to be able to watch this

we need to be able
to understand how life is.

Compared to this ant, a human cell

is about a hundred million
times smaller in volume.

Do you see the cell
that's right next to this ant?

It's right there.

To be able to watch this cell,

we need to make the invisible visible,

and we do this by building microscopes.

Not these microscopes:

the ones that we build
look something like this.

It helps that I'm part
of a paparazzi, well, of sorts.

Instead of taking pictures of people,

I'm more interested
in taking pictures of famous cells.

Well, my own career path
up until this moment in time

has been pretty windy,

starting with my first childhood obsession
and continued passion in computer science,

which took a sharp transition

to looking at engineering,

and more recently

a very sharp transition

to trying to understand cell biology.

Now, it's these combination of disciplines

that has led me to where I am today.

I'm able to carry out
interdisciplinary research

with one clear goal,

and the idea is to be able
to advance innovation and discovery

by bringing together experts
from these different disciplines

to be able to work together
and solve problems that each of us can't.

Now, we're interested
in understanding the cell.

The cell... what is it?

Well, it's the fundamental unit of life.

Simply put, it's just a bag.

It's a bag that has trillions
of inanimate molecules,

whether it's proteins,
carbohydrates, lipids or fat.

And it turns out,
over the past half a century,

molecular biologists and biochemists
have figured out ways

to make these proteins glow.

They light up just like fireflies.

Now, microscope developers

have been able to make
better and better instruments

to be able to capture this light
emitted from these molecules,

and computer scientists and mathematicians

have been able to understand
the signals that are being recorded

from the cameras.

And by bringing these tools together,

we're actually being able to understand
the organization of these molecules

inside of these cells,

understand how that changes over time,

and that's essentially
what we're interested in,

trying to understand life at its essence.

So we want to go from imagine life,

which has traditionally
been confined to two dimensions,

to being able to image life
in three dimensions.

So how do you make a two-dimensional image
into a three-dimensional image?

Well, turns out
it's pretty straightforward.

We just collect a series
of two-dimensional images

as we're moving the sample up and down,

and then we stack the images
on top of each other,

and then you create
a three-dimensional volume.

The problem with this approach

is that traditional microscopes,

they dump way too much
energy into the system.

That means that this cell
that you see over here,

it's experiencing a lot of light toxicity,

and that's a problem.

Let me explain that a little bit better.

For example,

let's say that on this planet,
life evolved under just one sun, yes?

Now, let's say I wanted
to watch the shoppers on this street

to understand their shopping habits:

how long they linger in front of stores,

window shopping,

how many stores they go into,

and how long they spend
inside of each of the stores.

And if I was sitting down
at a coffee shop just people-watching,

many wouldn't even notice
that I'm watching them.

Now, what if all of a sudden

I was shining the equivalent
of what is, say,

the light, or the sunlight,
from about five

or, say, 10 different suns?

Would they still behave
as they normally did?

Would they still linger outside
for just as long?

Can I really believe that their behavior
hasn't been altered as a consequence

of being exposed to this much sunlight?

No.

Most microscopes these days,

and conventional microscopes,

have been able to dump

between 10 to 10,000 times the sunlight
that we're exposed to on this planet

where life actually evolved.

And because of this,

well, turns out I'm part
of the cell paparazzi,

so we need to be very careful
in terms of how much light

we actually put into the cell.

Otherwise, we might end up
with a deep-fried cell.

And turns out, there's really
nothing natural

about trying to watch a damaged cell

whose behavior has been
significantly altered.

Well, let's take this cell for example.

It's sitting on a piece of glass.

You see the spots everywhere?

Those spots represent molecular machines

that are assembling
on the surface of the cell

in order to be able to shuttle food
from outside the cell into the cell.

Our lab uses something called
the lattice light sheet microscopy,

which generates a very,
very thin sheet of light,

paying attention not to damage the cells

or not to put too much light
into the system.

And when we do this,

we're able to watch the dynamics
of that process for much longer

without really stressing out these cells.

We've used this microscopy technique

and tools to be able to understand
how viruses infect cells.

In this example, we've exposed
the cell to rotavirus.

It's an extremely contagious pathogen
that kills over 200,000 people every year.

And by watching these molecules,
these virus particles,

how they diffuse
on the surface of the cells,

we can actually understand
the rules that they're playing by,

and when we understand these rules,

we can start to outsmart them,

whether through
intelligent drug therapies,

to be able to mitigate, manage,
or even prevent the virus

from binding into the cell
in the first place.

Now, we've made the invisible visible,

but the question remains,

when can we believe what we actually see?

Everything I've shown you up until this point has been a cell that's been held prisoner on a piece of glass or in a petri dish. Well, it turns out that cells didn't really evolve on a piece of glass. Right? They didn't evolve in isolation, and they didn't evolve outside their physiological context. To truly understand cells' natural behavior, we need to able to watch them in action where actually is their home turf. So, let's take a look at this complex system. This is a developing zebrafish embryo, where you're looking at cells that are organizing themselves in order to form tissues, in order to form organ systems. And when we watch the movie again, you'll see that at about 20 hours, you start to form the eye and the tail of the zebrafish. Now, we can watch this, not in this low resolution, we can watch this in exquisite detail, and we want to be able to watch this in three dimensions over the course of minutes, seconds, hours, or even days. So the problem with these complex systems is that we scramble, or they scramble the light that we actually shine on to them, which causes us to record very blurry images. And it turns out that astronomers have had a similar problem, but for them the problem comes when they're trying to record the light from distant stars on telescopes that are ground-based. The problem is, when the light travels thousands of light years and it hits our turbulent atmosphere all of a sudden, the light gets scrambled. They've always luckily figured out a solution to this for over half a century. What they do is they generate an artificial star about 90 kilometers above the Earth's surface, and they use that light, which passes through the same turbulent atmosphere as the distant star's light, and they're able to understand how the light is getting scrambled, and they take a mirror that can change its shape in order to compensate or undo that scrambling. So what we've done is we have taken those ideas and we've implemented that with our microscope system, and when you do that you can more or less unscramble the complexity of the scrambling and the fuzziness that's happening as a consequence of complex systems. And we do this in zebrafish. We like zebrafish because, like us, they're vertebrates. Unlike us, they're mostly transparent. That means that when we shine light on them, we can watch the cellular and the sub-cellular dynamics with exquisite detail. Let me show you an example. In this video, you're watching the spine and the muscle of the zebrafish. We can look at the organization of the cells, hundreds of cells in this particular volume, in the presence and absence of adaptive optics. Now, with these tools, we can watch more clearly than we've ever been able to before. And in a very specific example, looking at how the eye develops in the zebrafish, you can really see the commotion inside of this developing zebrafish embryo. So you can see the cells that are dancing around. In one example, you see how the cell is dividing. In another example, you see cells trying to get places and squeezing past another cell. And in the last example, you see a cell being completely rowdy to its neighbors by just punching its neighbors. Right? This technology really enables us to watch deeper and more clearly almost as if we are watching single cells on a piece of glass where they have been held prisoner. And to demonstrate the promise that this technology holds, we've partnered with some of the best scientists from around the world. And we've started to ask a range of fundamental questions that we're starting to work on right now together. For example, how does cancer spread through the body? In this example, you're looking at human breast cancer cells that are basically kind of migrating, where they're using the blood vessels that are shown in magenta, they're basically using these blood vessels as highways to move about the cabin. You can basically see them squeezing through the blood vessels. You can see them rolling where there's enough space. And in one example, well, you see what looks like Ridley Scott's trailer for the next Alien movie. This cancer cell is literally trying to claw its way out of the blood vessel in order to invade another part of the body. In the last example I'm going to show you, we're trying to understand how the ear develops. In this case, we were completely upstaged by crawling immune cells. These immune cells are basically on patrol all the time. Basically, they don't get any time off. They're working constantly to understand whether there's stranger danger, trying to understand whether there's an infection.