How a longforgotten virus could help us solve the antibiotics crisis Alexander Belcredi
Take a moment
and think about a virus.
What comes to your mind?
An illness?
A fear?
Probably something really unpleasant.
And yet, viruses are not all the same.
It’s true, some of them cause
devastating disease.
But others can do the exact opposite –
they can cure disease.
These viruses are called “phages.”
Now, the first time I heard
about phages was back in 2013.
My father-in-law, who’s a surgeon,
was telling me about a woman
he was treating.
The woman had a knee injury,
required multiple surgeries,
and over the course of these,
developed a chronic
bacterial infection in her leg.
Unfortunately for her,
the bacteria causing the infection
also did not respond
to any antibiotic that was available.
So at this point, typically, the only
option left is to amputate the leg
to stop the infection
from spreading further.
Now, my father-in-law was desperate
for a different kind of solution,
and he applied for an experimental,
last-resort treatment using phages.
And guess what? It worked.
Within three weeks of applying the phages,
the chronic infection had healed up,
where before, no antibiotic was working.
I was fascinated by this weird conception:
viruses curing an infection.
To this day, I am fascinated
by the medical potential of phages.
And I actually quit my job last year
to build a company in this space.
Now, what is a phage?
The image that you see here was taken
by an electron microscope.
And that means what we see on the screen
is in reality extremely tiny.
The grainy thing in the middle
with the head, the long body
and a number of feet –
this is the image of a prototypical phage.
It’s kind of cute.
(Laughter)
Now, take a look at your hand.
In our team, we’ve estimated
that you have more than 10 billion phages
on each of your hands.
What are they doing there?
(Laughter)
Well, viruses are good at infecting cells.
And phages are great
at infecting bacteria.
And your hand, just like
so much of our body,
is a hotbed of bacterial activity,
making it an ideal
hunting ground for phages.
Because after all, phages hunt bacteria.
It’s also important to know that phages
are extremely selective hunters.
Typically, a phage will only infect
a single bacterial species.
So in this rendering here,
the phage that you see
hunts for a bacterium
called Staphylococcus aureus,
which is known as MRSA
in its drug-resistant form.
It causes skin or wound infections.
The way the phage hunts is with its feet.
The feet are actually extremely
sensitive receptors,
on the lookout for the right surface
on a bacterial cell.
Once it finds it,
the phage will latch on
to the bacterial cell wall
and then inject its DNA.
DNA sits in the head of the phage
and travels into the bacteria
through the long body.
At this point, the phage
reprograms the bacteria
into producing lots of new phages.
The bacteria, in effect,
becomes a phage factory.
Once around 50-100 phages have accumulated
within the bacteria cell,
the phages are then able
to release a protein
that disrupts the bacteria cell wall.
As the bacteria bursts,
the phages move out
and go on the hunt again
for a new bacteria to infect.
Now, I’m sorry, this probably
sounded like a scary virus again.
But it’s exactly this ability of phages –
to multiply within the bacteria
and then kill them –
that make them so interesting
from a medical point of view.
The other part that I find
extremely interesting
is the scale at which this is going on.
Now, just five years ago,
I really had no clue about phages.
And yet, today I would tell you
they are part of a natural principle.
Phages and bacteria go back
to the earliest days of evolution.
They have always existed in tandem,
keeping each other in check.
So this is really the story of yin
and yang, of the hunter and the prey,
at a microscopic level.
Some scientists have even estimated
that phages are the most
abundant organism on our planet.
So even before we continue
talking about their medical potential,
I think everybody should know
about phages and their role on earth:
they hunt, infect and kill bacteria.
Now, how come we have something
that works so well in nature,
every day, everywhere around us,
and yet, in most parts of the world,
we do not have a single drug on the market
that uses this principle
to combat bacterial infections?
The simple answer is: no one
has developed this kind of a drug yet,
at least not one that conforms
to the Western regulatory standards
that set the norm
for so much of the world.
To understand why,
we need to move back in time.
This is a picture of Félix d’Herelle.
He is one of the two scientists
credited with discovering phages.
Except, when he discovered them
back in 1917, he had no clue
what he had discovered.
He was interested in a disease
called bacillary dysentery,
which is a bacterial infection
that causes severe diarrhea,
and back then, was actually
killing a lot of people,
because after all, no cure for bacterial
infections had been invented.
He was looking at samples from patients
who had survived this illness.
And he found that something
weird was going on.
Something in the sample
was killing the bacteria
that were supposed to cause the disease.
To find out what was going on,
he did an ingenious experiment.
He took the sample, filtered it
until he was sure that only something
very small could have remained,
and then took a tiny drop and added it
to freshly cultivated bacteria.
And he observed
that within a number of hours,
the bacteria had been killed.
He then repeated this,
again filtering, taking a tiny drop,
adding it to the next batch
of fresh bacteria.
He did this in sequence 50 times,
always observing the same effect.
And at this point,
he made two conclusions.
First of all, the obvious one:
yes, something was killing the bacteria,
and it was in that liquid.
The other one: it had to be
biologic in nature,
because a tiny drop was sufficient
to have a huge impact.
He called the agent he had found
an “invisible microbe”
and gave it the name “bacteriophage,”
which, literally translated,
means “bacteria eater.”
And by the way, this is one
of the most fundamental discoveries
of modern microbiology.
So many modern techniques go back
to our understanding of how phages work –
in genomic editing,
but also in other fields.
And just today, the Nobel Prize
in chemistry was announced
for two scientists who work with phages
and develop drugs based on that.
Now, back in the 1920s and 1930s,
people also immediately saw
the medical potential of phages.
After all, albeit invisible,
you had something
that reliably was killing bacteria.
Companies that still exist today,
such as Abbott, Squibb or Lilly,
sold phage preparations.
But the reality is, if you’re starting
with an invisible microbe,
it’s very difficult to get
to a reliable drug.
Just imagine going to the FDA today
and telling them all about
that invisible virus
you want to give to patients.
So when chemical antibiotics
emerged in the 1940s,
they completely changed the game.
And this guy played a major role.
This is Alexander Fleming.
He won the Nobel Prize in medicine
for his work contributing
to the development
of the first antibiotic, penicillin.
And antibiotics really work
very differently than phages.
For the most part, they inhibit
the growth of the bacteria,
and they don’t care so much
which kind of bacteria are present.
The ones that we call broad-spectrum
will even work against
a whole bunch of bacteria out there.
Compare that to phages,
which work extremely narrowly
against one bacterial species,
and you can see the obvious advantage.
Now, back then, this must have felt
like a dream come true.
You had a patient
with a suspected bacterial infection,
you gave him the antibiotic,
and without really needing to know
anything else about the bacteria
causing the disease,
many of the patients recovered.
And so as we developed
more and more antibiotics,
they, rightly so, became the first-line
therapy for bacterial infections.
And by the way, they have contributed
tremendously to our life expectancy.
We are only able to do
complex medical interventions
and medical surgeries today
because we have antibiotics,
and we don’t risk the patient
dying the very next day
from the bacterial infection that he might
contract during the operation.
So we started to forget about phages,
especially in Western medicine.
And to a certain extent, even when
I was growing up, the notion was:
we have solved bacterial infections;
we have antibiotics.
Of course, today,
we know that this is wrong.
Today, most of you
will have heard about superbugs.
Those are bacteria
that have become resistant
to many, if not all, of the antibiotics
that we have developed
to treat this infection.
How did we get here?
Well, we weren’t as smart
as we thought we were.
As we started using
antibiotics everywhere –
in hospitals, to treat and prevent;
at home, for simple colds;
on farms, to keep animals healthy –
the bacteria evolved.
In the onslaught of antibiotics
that were all around them,
those bacteria survived
that were best able to adapt.
Today, we call these
“multidrug-resistant bacteria.”
And let me put a scary number out there.
In a recent study commissioned
by the UK government,
it was estimated that by 2050,
ten million people could die every year
from multidrug-resistant infections.
Compare that to eight million deaths
from cancer per year today,
and you can see
that this is a scary number.
But the good news is,
phages have stuck around.
And let me tell you, they are not
impressed by multidrug resistance.
(Laughter)
They are just as happily killing
and hunting bacteria all around us.
And they’ve also stayed selective,
which today is really a good thing.
Today, we are able to reliably identify
a bacterial pathogen
that’s causing an infection
in many settings.
And their selectivity will help us
avoid some of the side effects
that are commonly associated
with broad-spectrum antibiotics.
But maybe the best news of all is:
they are no longer an invisible microbe.
We can look at them.
And we did so together before.
We can sequence their DNA.
We understand how they replicate.
And we understand the limitations.
We are in a great place
to now develop strong and reliable
phage-based pharmaceuticals.
And that’s what’s happening
around the globe.
More than 10 biotech companies,
including our own company,
are developing human-phage applications
to treat bacterial infections.
A number of clinical trials
are getting underway in Europe and the US.
So I’m convinced
that we’re standing on the verge
of a renaissance of phage therapy.
And to me, the correct way to depict
the phage is something like this.
(Laughter)
To me, phages are the superheroes
that we have been waiting for
in our fight against
multidrug-resistant infections.
So the next time you think about a virus,
keep this image in mind.
After all, a phage might
one day save your life.
Thank you.
(Applause)