A Virus-Resistant Organism -- and What It Could Mean for the Future | Jason W. Chin | TED

So we built a virus-resistant organism.

Why?

It's not about disease, or not directly.

It's about building the clean factories of the future.

Let me explain by taking a big step back.

All life runs on DNA.

DNA codes for proteins, and proteins run life.

DNA is composed of four bases:

A, T, G and C.

And triplets of these bases, known as codons,

encode each of the amino acid building blocks in proteins.

The genetic code is a rulebook

that defines which codon encodes which amino acid.

So, for example,

the triplet codon TCG encodes the amino acid serine.

And the order of triplet codons in DNA

encodes the order of amino acid building blocks in a protein.

There are 64 triplet codons in DNA

and just 20 common amino acids.

And this means that most amino acids

are encoded by more than one triplet codon.

So, for example, the amino acid serine

is encoded by six different triplet codons.

And triplet codons that encode the same amino acid

are defined as synonymous codons.

The DNA code used for life is near universal.

All forms of life and viruses use essentially the same genetic code.

And that's a trait that we can exploit.

Here's what we did.

We asked whether life needs multiple synonymous codons

to encode a single amino acid.

For example, does life need six different codons,

which all code for the amino acid serine?

We took the four-million-character DNA of E. coli, its genome,

and completely rewrote the code of this microbe

in a very specific way

by replacing targeted codons in its genome

with synonymous codons that encode the same amino acid.

So for example,

we replaced the TCG and TCA codons,

which encode the amino acid serine,

with AGT and AGC codons,

which also encode the amino acid serine.

By doing this across the whole four-million-base genome,

we completely removed the targeted codons from the genetic code of E. coli.

Overall, we compressed the genetic code from using 64 codons to using 61 codons.

How did we do it?

We first took the four-million-character code in a computer

and used a find-and-replace operation

to replace targeted codons with their synonyms.

This created our new genome design,

which contained more than 18,000 changes with respect to the original genome.

We then asked whether we could build an organism

that runs on our synthetic genome design.

We built the synthetic genome starting from short pieces of DNA.

These were made by chemistry in a test tube,

something that would have been prohibitively expensive to do

on this scale just a decade or two ago.

We then assembled these short pieces of DNA

into longer stretches of DNA,

which we then used to step-by-step replace

all four million bases of the E. coli genome.

This created the largest synthetic genome ever made.

And the resulting cell was alive.

Think about that.

We streamlined the genetic code, and yet the cell lived.

We can create life with a compressed genetic code.

Now because our organism with a compressed genetic code

doesn't use all 64 triplet codons to make proteins,

we could remove some of the machinery from the cell

that normally reads the near-universal genetic code.

Specifically, we could remove components of the translational machinery,

specific tRNAs,

that normally read the codons that we've removed from the genome.

Now, the key point here is that we've created a cell

that no longer reads all the codons in the near-universal genetic code.

Now viruses infect cells.

These might be the cells of our bodies

or single-celled microbes like E.coli.

They commonly have their own DNA,

which uses the near-universal genetic code

to encode the proteins necessary to make copies of the virus.

But viruses don't have the machinery to read the genetic code in their DNA,

and instead they rely on the host cell, the machinery of the host cell,

to read the genetic code in their DNA

and make copies of the virus.

It's these copies of the virus that go on to infect other cells.

And this is how viruses spread.

But viruses are unable to make copies of themselves in our new organism

because our new organism doesn't have the machinery

to read all the codons in the DNA of the virus.

The code in the DNA used in the virus

and the host cell's machinery to read that code are incompatible.

Therefore, the virus doesn’t spread in the new organism,

and the new organism is resistant to viruses.

In fact, we showed that our new organism was resistant to a wide range of viruses,

suggesting that rewriting the genetic code

provides a route to creating broadly virus-resistant life.

By extending the approaches we've developed to other organisms,

it may be possible to create virus-resistant crops and animals

with important applications in agriculture and beyond.

But our advances also provide a foundation

for turning cells into the clean factories of the future.

How?

So to explain, let me take another step back

to how organisms read their genetic code to make proteins.

Recall that the order of triplet codons in DNA

encodes the order of amino acid building blocks in a protein.

And it's the translational machinery of cells

that reads the triplet codons

and builds the corresponding sequence of amino acids.

The translational machinery of natural cells --

including ribosomes,

aminoacyl-tRNA synthetase enzymes and tRNAs --

is a unique and special system for making proteins

in which the 20 common amino acids are strung together in a chain.

Now, proteins are amazing,

but they're just one example

from a vast class of molecules known as polymers,

which includes plastics, materials and drugs.

And the polymer or linear polymer is really any molecule

in which simpler chemical building blocks are strung together in a chain.

We wanted to unlock the potential of the translational machinery

for making plastics, materials and drugs

that simply can't be made in any other way,

or that could be made more cleanly and efficiently

using engineered versions of the cell's translational machinery.

The building blocks for these polymers

go well beyond the 20 common amino acids used to make proteins.

It's been impossible to unlock the potential

of the translational machinery for making plastics, materials and drugs

for two reasons.

First, all 64 triplet codons in natural cells

are used for making natural proteins,

and there are simply no codons available to encode the synthesis of new polymers.

Second, the natural translational machinery

specifically uses natural amino acids

and simply can't use the chemical building blocks

required to make new polymers.

However, a virus-resistant organism

doesn't use all 64 triplet codons to make proteins

and doesn't contain the machinery to read the codons

that have been deleted from its genome.

And this cell provides the starting point for genetically-encoded polymer synthesis.

To realize genetically-encoded polymer synthesis

in our virus-resistant organism,

we added synthetic DNA containing the triplet codons

we'd removed from the genome of the cell

and engineered translational machinery to read these codons

and reassign them to new chemical building blocks for new polymers.

This system can be programmed to make diverse synthetic polymers.

By changing the order of the triplet codons

in the synthetic DNA,

we can change the order of the chemical building blocks

that we program into the resulting polymer.

And by changing the identity of the engineered translational machinery

that we add to the cell,

we can change the identity of the chemical building blocks

from which we compose the polymer.

Overall, we've created a cellular factory

that we can reliably and predictably program

to make synthetic polymers.

Using our approach, we've already been able to program cells

to make new molecules,

including molecules from an important class of drugs

known as depsipeptide macrocycles.

Molecules in this class include antibiotics,

immunosuppressives and anti-tumor compounds.

We've also been able to program cells to make completely synthetic polymers

containing the chemical linkages found

in several classes of biodegradable plastics.

As we build new polymer molecules using our cellular factories,

we have the opportunity to consider from the beginning

how we might also use engineered biological cells

to break these polymers down

into their constituent chemical building blocks

that could be recycled and used for new encoded polymers.

We envision a circular bioeconomy

in which our new genetically-encoded plastics and materials

are manufactured and ultimately broken down

using low-energy cellular processes,

taking advantage of existing bioreactors and fermenters.

By taking inspiration from nature and reimagining what life can become,

we have the opportunity to build the sustainable industries of the future.

Thank you.

(Applause)