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.