Translator: Ivana Krivokuća Reviewer: Mile Živković
Medicines are essential for our quality of life,
and yet, we lack safe and effective medicines
for many of our most pressing diseases and conditions.
Many of these limitations are very closely tied
to how we get our medicines.
What you're looking at is digoxin,
which is a medicine that's used to treat heart failure.
This medicine is obtained from the foxglove,
which is an ornamental plant that is commonly found in gardens.
In fact, over half of our medicines are obtained from nature,
and a very large fraction of those are obtained from plants.
You can imagine that relying on nature to provide our most important medicines
comes with many challenges.
The first is that nature is imperfect.
These plants take a very long time to grow,
oftentimes over the course of a year,
and during that time, they're subjected to variations in weather,
to disease and pests,
all of which can affect the amount and the quality of medicine
that's available in any given year.
The second is that most of our most valuable and needed medicines
are not going to be provided by nature.
These plants are not making these compounds as medicines for us;
they're making these compounds for their own purposes,
oftentimes for defense, and what that means is that
there's just a large set of medicines that we're not going to be able
to source from nature.
The third is that most of the people on this planet, still to this day,
have insufficient access to medicines.
With all of these challenges, you might wonder wouldn't it be better
if we could actually just go in and make our own medicines.
We took that question and we said,
"Okay, let's start with one of the most complex family of medicines out there".
This is a class of compounds that has evaded decades of research
in the laboratory in terms of trying to arrive at better solutions.
We said, "Could we develop an approach that's grounded in biotechnology,
that would address a lot of the challenges that arise
when we rely on nature to source our medicines?"
What you're looking at is the opium poppy.
It's from this plant that we get many of our most effective pain medicines.
We used this as our starting point.
I want to start by discussing the scale of what's required
to source medicines from nature.
There's about 800 tons of opiates that are sourced annually
to make our painkillers.
What this equates to in terms of land usage
is about 100,000 hectares of land that's farmed for poppies.
You can think about this roughly as the size of Rhode Island.
Because poppies require a very specific climate to grow,
and also because of the regulation associated with growing these crops,
what it means is that there's a very small number
of geographical regions on our planet where poppies are grown.
Over half of these come from Australia.
Finally, still to this day, the large majority of people on our planet
have insufficient access to pain medicines to treat moderate and severe pain.
Let's look in a little bit closer
at what this manufacturing platform actually looks like.
There are many steps from the point at which we get or medicinal opioids
to the point of the poppy.
Essentially, this plant is producing one particular compound, morphine,
and it's making this compound as a very, very small fraction
of the overall plant material.
So we have to go into the plant
and basically remove this compound so that we can use it as a medicine.
That will require us to use fairly toxic chemicals to do that.
Because these plants are being grown oftentimes, very far distances
from where the medicine is actually being used,
we then have to take very large volumes of narcotic material
and transport it very long distances
to where the medicines will ultimately be used.
Then, finally, because the poppy is not making the most valuable pain medicine,
we have to take the compound that we get from poppy - morphine -
and then subject it further to chemical processing steps
to allow it to be converted into higher value,
more effective pain medicines.
The next challenge that arises
is that this medicinal plant is not just making opiates;
it's making a number of other compounds
that we have great interest in to treat other types of diseases
such as cancer and neurodegenerative disorders and hypertension.
So we'd like to be able to go into this plant
and retrieve these molecules as well.
But the plant is making these as a very complex mixture.
It's making all these different compounds together.
That adds a lot of cost and complexity in terms of,
once we retrieve the compounds, trying to separate them,
so that we have purified amounts of each of the compounds
that we can then use as medicines and ultimately those challenges
will limit our access to those other types of medicines.
Then finally, as many of us are aware of,
this type of manufacturing feeds directly into an illegal market,
where poppies can be farmed and fed into the heroin market.
It's also the case that we have abuse of these medicinal opioids.
We started this journey about ten years ago.
We asked a seemingly simple question,
which was: could we shift from a manufacturing platform
that was based on growing vast amounts of a drug crop,
and instead ask a simple single-celled organism,
like baker's yeast, to make compounds that we could use as medicines directly,
that would have improved properties.
I want to start with an overview of what this process actually looks like.
Again, what we're essentially trying to do is move from the sort of one organism,
one compound that that organism has evolved to make,
to one in which we actually go in to the broader natural world
and begin to look at the different organisms
that are present on our planet and search for activities that we believe
would be of interest in making the perfect medicine.
We can begin to look at different organisms,
we can pull out activities that we believe will be of interest,
and then we can take those activities that are distributed
in different organisms throughout nature,
and begin to combine them into a new single organism,
in this case, baker's yeast.
At the end of that, what we'll have is an organism that now has
these activities combined in ways that you don't find in nature.
We can now grow this organism very inexpensively,
and over a period of several days.
This organism will be able to provide for us
new sets of medicines that we can't find in nature.
Now that we've kind of looked at it at a high level,
let's zoom in to some of the details of what this actually means.
At this level, it's useful to think of the process
that's going on inside the yeast
as this really complex molecular assembly line,
where this assembly line is essentially taking the sugar that we feed yeast
as a building block, and then it's building it up
into a complex medicinal compound that we can then use.
The first challenge that happens is that, in addition to sort of coaxing yeast
into making this really complex assembly line,
the next challenge we're confronted with is the fact that oftentimes
many of the components that we would like to be able to use
to build this assembly line,
we simply don't know what they are; we haven't found them.
This presents us with our first challenge.
How do we build within an environment that we just don't know actually,
what we're asking the yeast to make?
The way that we do this is that we go back into nature
and we began to go and search the genomes of those different organisms.
Essentially, what we're doing is we're looking at the DNA sequences
of many different organisms,
and that sequence essentially holds the directions
for how those organisms make different activities
that we believe will be of interest to make new medicines.
We can use computational tools that will search those DNA sequences
and essentially identify its subsets of the DNA sequence
that we believe encodes interesting activities.
Once we identify those subsets of sequences,
we can simply take that DNA sequence, move it into our yeast host,
and begin to test directly whether the activity
is actually what we hoped it would be
and whether it will work to build our medicine.
This leads to the second challenge that then comes up.
You can imagine that plants and yeast are very different organisms.
We're basically taking components
that have evolved over many thousands of years
to work within plants, which is a very particular environment,
and asking them to move directly over into yeast
and give us the desired function.
The challenge that arises is that oftentimes that just doesn't work.
The components aren't made correctly, they don't function within the yeast host,
and then this presents us with the next challenge,
which is: how do we sort of combat against these thousands of years of evolution
that have worked to very specifically tune and perfect the activity
of these components within one environment,
and be able to rapidly move it over into our other organism of interest?
The way that we solve this is we essentially develop
the tools that allow us to recode the instructions and directions
so that yeast can read them.
What this essentially means is if we return to the bioactivities
that I talked about, that we identify from different organisms in nature,
we have to go in and take that DNA sequence information,
and basically completely rewrite it.
We're rewriting it so that yeast now is able to read it
and make the active components within its own environment.
They make them in a way that they can then assemble
into these assembly lines within yeast,
to be able to efficiently convert the building blocks
to the medicinal compounds.
At the end of this process, what we have is a very engineered organism.
The yeast that are able to convert sugar to medicinal opioids
have been engineered to make 23 synthetic proteins,
and these have been taken from six different organisms.
What's notable about this engineering feed in and out of itself
is that we're now at the stage where we can go into nature,
pull large numbers of proteins from different organisms,
and move them into an entirely different organism
from any of them that we pulled from, to create the perfect beast.
In doing this, we're now able to move beyond the molecules
that opium poppy gives us naturally,
and directly make improved medicines for our therapeutic use.
The importance of this technology then
is not just that we've developed an improved process
for making one particular class of a very important medicine,
such as painkillers,
but that in tackling this challenge
for one of the most complex family of molecules out there,
we're now able to rapidly apply this technology
to build any molecule of interest,
and even more importantly,
we can apply the technology to go beyond what we find in nature
to create better medicines with improved therapeutic activities,
and reduce negative side effects.
What you essentially have here is a platform
that is changing our relationship with medicines and with nature.
The final question is:
is this it, are we able to completely declare victory?
The answer is: not yet.
But this is a long journey, and there are many steps within this journey.
The incredible news is that we're now at the point with the technology
that within the next year we'll be able to partner with pharmaceutical companies
to bring this technology to market in a rapid time frame,
that will impact people's lives.
But it's also really important to understand
that there's a lot of very important work that's left for us to do
to be able to take this technology and broadly develop new medicines
and make them available to everyone on this planet.
Thank you.
(Applause)