Reprogramming viruses as biomolecular computers: Junghae Suh at TEDxRiceU

I think we can all pretty much agree

that germs are really annoying.

You can take my word for this
because I'm kind of an expert.

Not only because I work
with viruses for a living,

which I do,

but mainly because I have
two young sons at home.

They're four and two,

and I swear they are germ factories.

It seems like every single week
they are sick with something.

They have some upper respiratory,

lower respiratory, diarrhea, vomiting,

you name it, they've been infected.

What that means is I am constantly sick.

So, yes, germs are a real big pain.

But luckily if it's a bacterial infection

you can treat it with antibiotics,

but if it's a viral infection

you just kind of wait it out, right?

But luckily most of the infections
are not that bad

and my kids will cure them
in a couple of weeks.

But we also know
that there are a lot of other viruses

that lead to more significant problems.

It can range from maybe
having life-long cold sores

to something more serious
like debilitation or even death.

So in general viruses are something

I want to stay away from.

They're nasty.

But now let me introduce you to my mom.

This picture was taken in December 2008.

We were visiting my brother,

who lived in Hawaii at that time.

My mom loves golf,
her family and warm weather.

Probably in that order.

So Hawaii is really her paradise.

We had a really great time,
it was really fun.

Unfortunately, when I took this picture,

I didn't realize that my mom's body

was in the process of betraying her.

Because just six months later
she was diagnosed with breast cancer.

When she was diagnosed,

I was pregnant with my first son.

So it became this big
emotionally confusing time for me.

Because there I was,

growing life in my body,

and there she was,

growing what could potentially

be her death.

And in addition, since I was pregnant,

I was starting to appreciate

the female breasts as something

that provides sustenance, right?

They're supposed to support life.

But hers may ultimately
be the source of her demise.

So it was a very difficult time.

In a couple months after her diagnosis,

she started her cancer treatment.

Chemo, surgery, radiation.

It was a very difficult time.

And all the things that you hear

about cancer treatment,
especially chemo being horrible,

it's true, it is really horrible.

And this is something
that you will not appreciate

unless you or someone you love
goes through it.

But we've made it.

We made it through that long, intense year

and at her cancer hospital

there's this bell
that they hung on the wall

and at the end of the year
you can go and ring that bell,

telling everyone
you're done with treatment,

you're done with cancer.

So we were very happy that day,

but that happiness and that relief

was extremely short-lived.

And the worry starts to creep in.

The source of that worry

is because of this one word.

This one word has so much power.

Metastasis.

Metastasis is where the cancer

that originated in one part of the body

spreads and moves
to different parts of your body,

to set up tumors elsewhere.

According to the American Cancer Society,

if the cancer cells
are found just in your breasts,

your 5-year relative survival rate
is 99 percent.

Which is great.

But you can see that if cancer cells

are found at distant metastatic sites,

your survival rate drops to 24 percent.

That is scary.

Hence, we have one
of the greatest challenges

to modern medicine.

Which is, how do we deliver
these toxic drugs,

these messages of death, if you will,

just to those metastatic cancer cells?

When we're talking about delivery,

there are really two factors
that you must consider.

One is efficiency.

How well can you get these drugs,
these messages of death,

just to the cancer cells, right?

And the second is specificity.

That's where you want those drugs

delivered just to the cancer cells,

those metastatic cancer cells,

but leave all the other
healthy tissues alone.

And that will decrease
those horrible side effects.

The question is, how?

In my work,
the answer lies with the virus.

Viruses are nature's nano-cell machines

that have evolved to deliver genes,

or deliver messages

into those cells.

They are incredibly good at their job.

So what we're trying to do

is engineer viruses to treat cancer.

Let me introduce you now

to the virus that we work on.

It's called the adeno-associated virus,

it's a very benign virus,

it is not linked to any disease.

Actually most of us,
80 to 90 percent of us

sitting here today,

we've already been infected by this virus.

So I'm showing you here
the outside shell of this virus.

It is empty on the inside,

so that it could carry
a very small piece of DNA

that encodes for that message

that you would want to deliver
to the cancer cells.

And so when I look
at images like this, of the virus,

I am convinced
that Mother Nature is an artist.

Not only that,
she is a proficient designer.

The tight interlock
between form and function

is fundamental for design.

This virus is only
25 nanometers in diameter,

which is 4,000 times smaller
than the width of your hair.

So, in this tiny little package,

Nature doesn't really
have a lot of wiggle room

to include things that are not important

for the ultimate function of the virus.

Which is to infect cells.

The other thing I want to point out

is that viruses are old technology.

I mean, it's really,
really old technology.

Billions of years.

What we're trying to do

is to simply piggy-back

on Mother Nature's work.

To program these viruses to kill cancer.

Our over-arching strategy, in our lab,

is to program synthetic algorithms

into the virus structure,

in order to train it to pick out

those cancer cells and to destroy them.

Now, it turns out, that you can already

think of viruses
as nanoscopic computers.

They have evolved to detect

biomolecular signals

in their environment,

which could include

biomolecular cues in our bodies,

in order to have productive infections

that lead to self-replication ultimately.

In every step
of the virus infectious process

the virus detects biomolecular signals

that allow the virus to do the next step

of that infection,

and t's actually very fascinating,

because it turns out that every

biomolecular signal acts upon the capsid,

changing it, sometimes just a little bit,

and sometimes quite dramatically.

So you can think of viruses

as some of the most primitive
shape-shifters.

In our work, we're basically taking

these intrinsic properties of viruses

as inspiration and we want to re-write

or re-program what the virus

detects and computes
as biomolecular input.

Here are some of the viruses

that we have re-programmed
in the laboratory.

Just by looking at them,

you actually won't be able
to tell the difference

between our engineered viruses

and the ones that exist in Nature.

But these are different.

These have algorithms

programmed into their structure

that turns them into
cancer-seeking assassins.

Let me explain.

The basic idea

is that we want to create viruses
that will be able

to travel throughout the body

in an inert fashion,

or in a locked configuration, if you will.

In this locked configuration

the virus cannot deliver the message

that it's carrying

until it comes across
some biomolecular cue,

signal, represented by the key here,

and that key will open up the capsid

and now, in this open configuration,

the virus can deliver that message

to the cancer cells.

The other way that I like to conceptualize

our design strategy is thinking of it

as if we were programming encryption

into these viruses.

So, the message cannot be read

unless it is deciphered
by the appropriate key.

The next natural question is, what key?

Luckily, advances in biomedical research

has been answering that question for us.

It turns out that if you look
at tumor cells,

tumor masses, there are a lot

of biochemical signals, these cues,

that are present at higher concentrations

in the tumor,
either outside of the cancer cells

or within the cancer cells themselves.

You can imagine all of these cues

can act as the key

that will open up our virus.

This is a demonstration of how

one of our devices work.

In this black part, you don't see anything

but there's an entire lawn of cells

and onto this lawn we've added
these viruses

that we have in here, and in this case

the virus is still in its locked state,

its encrypted state,

and as a demonstration
this virus is delivering a message

that, if read properly by that cell,

would turn that cell green.

It's a green message.

You can see there's really not many cells

that are able to read that green message.

That's mainly because
the virus is encrypted.

Conversely, when the virus sees

these biomolecular keys,

the viruses open,

that message is decyphered

and these cells can now read

these green messages.

Let's go back to the schematic here.

I told you that there's a lot of keys

within the tumor mass,

greater concentration in the tumor,

but you may have noticed
that there are also keys,

present at lower concentrations,

elsewhere in the body.

And that represents some problem.

That could lead to these
non-targeted side effects,

that you want to run away from.

Our answer to this is trying

to make these viruses open

only when it detects two,

both the red and the green.

As shown here.

And we have successfully generated

one of these devices recently.

Another way to think about this

is to program an "AND" logic operator

into this virus structure.

I believe that the virus
biotechnology community

we are dreaming the same dream,

we have the same vision.

In the very near future,

we want to be able to program viruses,

real viruses, as we would
computer programs.

And we want this design process

to be standardized, modular

and lead to a predictable outcome.

I leave you with a cliff-hanger.

The big looming question is,

how will these devices work
in the human body?

Will they actually do
what we are proposing?

We don't know the answers
to these questions yet.

But I work with a really great team,

of very hard-working
and passionate students

on this research.

So follow us and see our progress

over the next several years.

I invite you. Go viral with us.

Thank you.

(Applause)