The life unfolding inside your cells, revealed in 3D

To understand how life works, you need to watch it in action, says bioimaging scientist Gokul Upadhyayula. Taking us down to the cellular level, he shares the work behind cutting-edge microscopes that capture and record, in three dimensions, the complex behaviors of living organisms -- from infecting cancer cells to crawling immune cells -- and what they're revealing about the dynamics of biology. Watch life unfold before your eyes with the incredible visuals in this talk.

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 this 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 imaging 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 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 zebra fish 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 zebra fish.

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 the light,

or they scramble the light
that we actually shine onto 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 also, luckily, figured out
a solution to this

for over half a century.

What they do is they generate
an artificial star

at 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've 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 zebra fish.

We like zebra fish 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 subcellular dynamics

with exquisite detail.

Let me show you an example.

In this video, you're watching the spine
and the muscle of a zebra fish.

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 zebra fish,

you can really see the commotion inside
of this developing zebra fish 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're watching
single cells on a piece of glass

where they've 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 neutrophils.

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.

They're sensing the environment,
constantly moving around.

Now, we can watch these images
and these movies

in greater detail than has ever
been possible before in our time

up until now.

Now, as with all new technologies,

new capabilities come with new challenges,

and for us, the big one
is how we handle the data.

These microscopes generate a ton of data.

We generate anywhere from
one to three terabytes of data per hour.

To put that into context: we're filling up
two million floppy disks every hour,

for our more experienced audience members.

(Laughter)

Roughly equal, then, to about 500 DVDs,

or to put things into
better context for the Gen Z,

that's about a dozen iPhone 11s
that I'm filling up every hour.

We have a ton of data.

We need to find new ways
to be able to visualize this.

We need to be able to find new ways

to be able to extract
biologically meaningful information

from these data sets.

And more importantly,

we want to make sure that we can put
these advanced microscopes

into the hands of scientists
from all around the world.

And we're giving the designs
of these microscopes for free.

But the key important part is,

we need to collaborate even more
to make an impact.

We're bringing together scientists

who can develop new
biological and chemical tools.

We're working together
with data scientists

and instrumentation scientists

to be able to build and manage the data.

And because we're giving
these instruments out for free

for all academic and nonprofits,

we're also building advanced
imaging centers to house them,

to be able to bring together the group
of people that are microscopists,

that are the biologists
and the computational people,

and to build a team that's able
to solve the types of problems

that each of us individually cannot.

And thanks to these microscopes,

the frontier of science is open again.

So let's take a look together.

Thank you.

(Applause)