Transcriber: Chiara Polesinanti Reviewer: Elisabeth Buffard
All right, thank you, everybody.
It’s a pleasure to be here.
I want to start with a true story
of a very famous accidental discovery in science.
It goes something like this.
In 1928, Alexander Fleming was a Scottish physician and scientist
working in a microbiology laboratory in London.
He was doing his experiments,
he’s getting tired of the work,
and he decides to go back to Scotland for two weeks on vacation.
Unfortunately he wasn't the tidiest person
and he didn't clean up his experiments before leaving town.
When he comes back two weeks later,
he makes this amazing discovery
that a fungus had taken over some of his bacterial cultures.
And this was a surprise
because that fungus ended up killing the bacteria
in the intervening time that he was away.
No one had ever seen this before.
So this was a new discovery in science.
He ended up calling that chemical, that the fungus produced,
And that was the first antibiotic drug.
Soon after that,
in the decades that followed,
very many other physicians and scientists made similar discoveries,
and suddenly we had abundant numbers of chemical antibiotics
that could be used to cure bacterial infections in people.
So in this process of using antibiotics in earnest to help humans,
also it was determined that antibiotics could help animals.
So in domesticated agriculture,
there was plenty of use of antibiotics
to cure those diseases that those animals were facing.
But something else was done,
and that was simply adding antibiotics to the feed of these animals.
And it ended up that this made them larger, plumper
and better for meat production.
So all that describes how antibiotics were discovered
and then used in earnest around the world.
Great discovery for which,
when we’re using antibiotics that widely and with that much enthusiasm,
we actually created a problem
through a large experiment that was going on worldwide,
for which we didn’t know what the outcome would be.
It turns out if you expose bacteria to so many antibiotics
over such a long period of time,
they’ll evolve resistance to these chemicals
and they’ll be able to grow in their presence,
whereas before they had been able to kill the bacteria.
So now we face this increased rise of antibiotic resistance in bacteria.
So in the worst case scenarios, this is creating superbugs,
which you might have heard about in the news.
These are literally bacteria
that are resistant to all known antibiotics.
Through this process,
we can learn how evolution is indeed a very potent force in biology.
And in fact, there are few examples better than that one
of how evolution can actually impact your daily lives.
In the end, what we now call this is the antibiotic resistance crisis,
because only a few decades from now,
projection maps suggest that antibiotic resistant bacterial infections
will be a leading cause of death in the human population,
even exceeding the rates of death due to cancer, which are also on the rise.
So this is all very sobering news.
You might hear what I’m saying,
and imagine a world where you have an infection,
you go to your doctor for help,
and indeed, there are no drugs available
to solve the bacterial problem raging in your body.
Now, for some of us, this is actually not something far off,
it’s today.
And that is because there are plenty of humans
who are immune compromised
or they have diseases like cystic fibrosis
that leave them very vulnerable to bacterial infections.
And they’re already on the front lines of this crisis.
So we really are struggling right now to find some solutions to this problem
because it literally will start to impact every household.
What can we do about this?
For a long time, humans have looked to the biological creatures around us.
We’ve been inspired to find solutions to problems.
I can give you many examples.
One example is if you want to take a boat through water
rather than across water,
how would you design such a vessel?
We now call these submarines.
And it’s not accidental that they look almost identical
to large-sized ocean-dwelling creatures,
especially whales such as orcas.
So in this way, we’ve been inspired
by what has naturally evolved as traits in other creatures,
and we try and seize on that to solve problems
such as creating a submarine.
How can this help us in the antibiotic resistance crisis?
It turns out that there is this old proverb that says,
“The enemy of my enemy is my friend.”
Around the time that Fleming discovered accidentally penicillin,
other microbiologists made another impactful discovery,
and that is they find that there are tiny microbes --
this was in the early 1900s --
tiny microbes that are capable of killing bacteria.
So even though at that time
the microscopy didn't really allow them to see them very well at all,
they knew this was happening.
So this became a very impactful observation
because they realized, oh, well, perhaps phages could be used
to kill bacterial infections.
And this was the development of something called phage therapy.
You purposely take a virus --
a phage is a virus that is specific to only killing bacteria --
and you use that purposefully to try to cure an infection.
And in the early 1900s, this was done in humans and in animals.
However, despite what I’m saying has probably seeming to you good news,
there’s an important limitation to phage therapy,
and that’s really why it didn’t take off as a popular idea
at the time when we were discovering antibiotics
and how useful they would be in controlling infections.
And that is phages and bacteria have been together on this planet
for perhaps 3 billion years.
So it’s not surprising that facing all of this predation
that is caused by phages,
bacteria have evolved lots of mechanisms to withstand phage attack
and to avoid this kind of predation.
They’re very good at evolving away from the ability of phages to kill them.
So the expectation is that, yes, you could use phage therapy,
treating a patient,
if that patient has no other options,
such as no antibiotics, that would help them.
But you’d better be prepared for that to fail on you,
because you're essentially allowing the bacteria to see this phage
and perhaps evolve resistance to it.
So now we're left wondering, what could we do?
One thing that we could do is realize that bacteria
are almost like other prey items.
Imagine a lion hunting only specific types of prey, certain types of antelopes,
indeed, that’s what phages do,
they hunt and kill only specific types of bacteria.
So in the process of doing this, we do have a big limitation,
if the bacteria are evolving away from the phages.
We would like to do better
than the approach of “I’ll just find a phage,
I’ll administer it in therapy and I’ll hope for the best”
and say we have to expect that the phage is going to fail
due to the evolution of resistance to that phage attacking the bacteria.
So we really need to do something different.
And we’re trying to take bioinspired approaches to remedy this problem.
Now I’m going to begin explaining this innovation
and probably to you in a pretty weird way.
I’m going to have you think about human traits,
because what I want you to do is consider traits that humans have
that are sometimes liabilities,
and I’m going to do this to explain something called an evolutionary tradeoff.
So humans have lots of traits that distinguish us from other animals.
And one might ask,
Well, what are some things that humans do
that are actually outperforming other animals?
One is that we have the ability to hurl objects with speed and accuracy.
And you see this in some of the best of us
who have this task as professional baseball pitchers
or as very accomplished softball pitchers.
So how we are able to do this is that we’re the only great ape
that walks around on two feet all the time.
So we have an upper body musculature
that allows us to do all sorts of amazing tasks.
But there’s a problem with that,
which many of you are probably familiar with.
We place a lot of pressure on our neck and our lower back
because we’re on two feet all the time.
This can be very painful.
And in fact, in some people it could lead to chronic illness.
So the point here is to not look even far beyond humans
to understand that organisms can evolve to be very good at what they do,
but they might have some vulnerabilities along the way that could be exploited.
And this is what we thought about
when updating phage therapy for modern times:
could we use phage therapy and capitalize on the fact
that certain phages are going to be interacting with bacteria,
causing those bacteria to die, that’s the goal.
But if those bacteria evolve resistance to that phage,
I would like to make sure that the bacteria don’t get that for free.
I want them to get that because they’re going to suffer an evolutionary tradeoff
that’s going to make them more vulnerable to something,
but especially for us to care less about them as disease agents.
So how do we do this?
We first begin in the classic way of phage therapy,
as you go out in nature
and you look for viruses with interesting properties that can kill bacteria.
And that turns out to be an incredibly efficient process
because each time you go out and look for a new phage,
I'll guarantee you you'll find one.
Phages are the most numerous inhabitants of planet Earth,
and the vastness of their biodiversity is seemingly limitless
because every time we look for a new phage, we find one.
You literally find a new discovery in science.
So you can think of phages on this world as a vast, largely untapped resource
for bioinspiration.
Now we could just find any old phage to do the problem.
That’s the classic approach.
That’s not really good enough anymore.
We would like to find particular phages that have these tricks in their arsenal
so that they’re going to kill the bacteria
and then also drive those bacteria to suffer an evolutionary tradeoff.
We insist that bacteria cannot have their cake and eat it too.
So how to achieve this is,
indeed if you could find a phage that kills your bacteria,
causes these trade-offs to make them more vulnerable to something,
then you can get an upper hand.
You can create phage therapy in a modern way that is more long-lasting solution,
that’s more durable in the face
of the inevitabilities of bacterial evolution,
countering that phage predation and having it fail.
So we need a double-edged sword.
We need this to work when it works.
And we need it to work when it fails.
To illustrate this, in this innovation,
I want to give you more of a concrete example.
Certain bacteria are problematic for being antibiotic resistant,
because they have proteins that span the inner and outer portion of the cell,
creating something called a pump.
And that is, if antibiotics get into that cell,
they’re actively pumped out by these proteins.
So this is a very big deal,
because those bacteria are especially difficult to treat with antibiotics
as they become more and more resistant to antibiotics
through this ability to pump them out of the cell.
What we envisioned is that on planet Earth there must be phages
that have evolved naturally to bind to bacteria
by binding to these proteins in these pumps.
So why would we care about that?
So rather than the traditional phage therapy approach,
now we have something that we want to go look for,
and I’m going to predict that it’s going to drive an evolutionary tradeoff.
And that’s because these phages are attaching to key proteins of these pumps.
What's the obvious genetic solution for these bacteria?
Change that protein or discard that altogether.
And then suddenly,
you have bacteria that are incapable of pumping the antibiotics out
and they’ve been desensitized to antibiotics.
So in this way, we're able to not only kill the bacteria in a new way,
that’s an alternative to antibiotics, because we’ve updated phage therapy,
but we’re also reinvigorating our worsened antibiotic arsenal,
that’s not really effective anymore.
We’re taking useless drugs and making them useful again.
So that's the overarching goal.
And what I'm saying may sound like science fiction,
but it’s not,
because we can actually go out in nature
and find such phages that have naturally evolved on the planet.
What we quickly discovered alongside finding those phages
and characterizing them
is that already there are very many people
who are at the leading edge of the antibiotic resistance crisis,
they have problems now.
They have debilitating genetic diseases or other vulnerabilities to infection.
And indeed, they’re desperate for some help,
because antibiotics are not helping them anymore.
So it's very rewarding for me to say that the approach that I described,
we’ve already used it at least 20 times in hospitalized patients
who were suffering with multidrug
or what are called pain drug resistant infections,
or these superbugs are just not vulnerable
to any of our existing chemical antibiotics,
and we have to find another solution.
So as we do this work, we know that personalized medicine is wonderful,
but it’s not good enough.
The gold standard is to do what’s called a clinical trial,
where you want to identify healthy volunteers
who are vulnerable to these infections,
have them volunteer to take part in a trial and then observe,
ideally, that if they are given phages
to protect against infections with superbugs,
that it works.
And if they happen to become infected,
we would want to observe that those superbugs
deal with the phage predation problem
by evolving to avoid the phage
and then giving up some degree of antibiotic resistance
and converting to sensitivity.
So in this way, we revive useless drugs
and make them useful again.
So in conclusion,
what I’ve tried to convince you of is
a phage that we’re using now in the current day
and personalized phage therapy just might save your life one day
in a future world.
I’ve also tried to convince you that there’s lots of inspiration
from biodiversity on this planet.
We’ve seen in the past how traits that have evolved in other creatures
might be useful for us to harness those as ideas to solve problems innovatively.
And that’s certainly what we’re trying to do.
Moreover, microbiology is a great field
because you’re right at the front lines of an amazing biodiversity on this planet.
So what I’m hoping is that, in the near future,
we’ve got similar bioinspired ideas
to solve problems that seemingly are so difficult
that we’re really struggling in biomedicine right now
to solve those problems.
So the idea is that bioinspiration is going to take us there,
and that will hopefully be one way to address the antibiotic resistance crisis.
Thank you for your attention.