Transcriber: Trang Thu Dao Reviewer: Ido Dekkers
Allow me to introduce Mr. R.
Mr. R is a 55-year-old manager who’s worked in a high-stress environment
for over 30 years.
Now, Mr. R ends up at the hospital after feeling some kind of intense pains
in his chest, as well as a numbness in his left arm,
and the doctors inform him that he has suffered a heart attack
and needs to be hospitalized.
Here’s Mrs. L,
a mother of three, retired from teaching at an elementary school
Mrs. L starts experiencing shortness of breath,
as well as the weird pain in her jaw that spreads through her chest.
But at first doctor dismisses her, blaming her symptoms on menopause.
But the discomfort doesn't go away.
Mrs. L wants a second opinion,
and the second doctor tells her after some testing
that she has also suffered a heart attack.
And finally, here is Mr. M, a physics professor
with a special love for the croissants his wife makes.
Now, given his family history, he’s no stranger to cardiac adverse events.
So unfortunately, when he does feel the telltale signs of the chest pains,
he knows what it is as he's carted off onto an ambulance.
Now, all three of these patients have just suffered an acute event
called the myocardial infarction or heart attack.
But thanks to the wonders of medicine,
people are now saved from dying from heart attacks when they happen.
So the good news is that all three of them make it through life
and that's what matters to their family and friends.
But they're not out of the woods yet.
Now, science and by extension,
scientists such as myself are faced with a new problem.
The what comes after a heart attack?
The incidence of heart failure, which is a chronic disease
and amongst the most common afflictions worldwide,
has only gotten worse now that patients such as these survived the initial damage.
So really, the wonders of modern medicines have their limits,
and now currently the only way of managing heart failure is
through drug administration for the rest of your life.
Now back to our three patients, they all end up on the same medication,
even though the respective doctors aren’t really sure
what kind of clinical outcomes they will have
or how they will react to the drugs.
So let’s fast forward three months ahead
and look at the effects of this medication.
So Mr. R starts taking the medication and he immediately feels better.
His symptoms for heart failure subside, and he's almost back to normal.
Mrs. L, however, starts experiencing nausea, bloating, increased fatigue.
As a teacher, she’s always valued listening to the opinions of experts
and following the rules.
But despite her doctor’s insistence that this drug will absolutely work
after its successful clinical trial.
She actually stops taking the medication because she feels
all of the negative side effects and none of the benefits that she was promised.
Mr. M starts taking the medication, and he thinks he’s feeling somewhat better.
That’s good.
But then his doctor informs him that he has to change medications
and that they’re going to switch him on a new cocktail of very expensive treatments
in order to maximize the chances of stabilizing his condition.
So for Mr. M, the trial and error process starts all over again.
And on some days, he feels more like a guinea pig rather than a person.
Now, I've described to you three fictitious people,
but the reality is that millions of people worldwide
are coming into our hospitals and into our clinics with heart failure,
just like these patients or even other heart diseases.
And despite the many promising and might add very expensive clinical trials,
there’s no cure.
And more worryingly yet,
there is no universal treatment that works for everyone.
And this actually boils down to three main factors.
So first, we don’t sufficiently understand the patient-specific differences
that occur when we’re faced with heart injury or drug effects.
Number two, we test our drugs in a small sample of recruited patients,
which really fails to encapsulate the diversity and complexity of population
And three, we don’t actually have a very reliable model
in order to test their drugs before implementing them in humans.
So going back to the fundamentals, how do we model a heart?
How do we represent this beautiful, infinitely complex system
with thousands of blood vessels and different cell types?
How do we represent this machine that keeps our brain, our liver
every part of us alive?
And conversely, how do we model a diseased heart
because we need to study it in order to understand the tools,
the drugs that we need in order to repair it?
The truth is, we don't actually have that many tools,
so I'll go over the couple of
the couple of options that we have before we translate our basic science research
into a human.
So we have three options.
The first one is to use immortalized cell lines.
What are immortalized cell lines
Well. Someone a while ago took some cells from the heart, from a patient,
and these cells were actually modified in order to be able to grow.
And because they’re able to grow and expand contrarily to our usual heart cells
that are actually not able to grow.
We are able to sell them commercially throughout the world
to scientists such as myself,
and I’m able to do dozens, hundreds of experiments on these cells.
And that’s great.
But the problem is that the muscle like cells in the heart,
the ones that we have in our bodies are not able to grow.
they're not able to multiply.
So it really makes you question how accurate of a model that really is.
The second option is to use heart samples from patients.
So that involves going into the person's heart and collecting cells.
And if this sounds outlandish to you, it's because it absolutely is.
Imagine going up to a person whose heart works at 40 percent capacity
and telling them, I want a sample of your heart.
I want a sample of a tissue that inherently does not repair itself
for science.
That’s insane.
And of course, there’s also the problem that even though this is that
even though this is incredibly invasive,
it also has the added problem that’s inefficient.
Because the fact that these cardiomyocytes that are inside of our heart do not grow,
we would never be able to perform any kind of repeatable and meaningful experiments.
So that doesn’t really work either.
The third model that we have is an animal model, notably mice or rats,
but I don’t really need to remind you that rodents and humans don’t really look alike
From the patients that we’ve seen from the beginning.
We see that we’re not even able to draw significant conclusions
based on different people.
And let alone a smaller animal model that
has a physiology completely different to ours.
So the bottom line is that we're really not able to replicate this.
We’re really not able to replicate a model of heart failure
at a patient-specific level.
As it stands, the best that we’ve got is this
And I wish I could tell you right here with a straight face that it’s this
absolute passion for science emanating from me in this picture
that is going to usher in this new age of personalized cardiac repair therapies.
But that’s actually not it.
Unfortunately, it's what I'm holding in my hand, which is a dish and what's.
And this dish, more precisely what’s inside of it is at the heart of my work.
So right here, I'm actually trying to generate a cell model,
but that is very specific to patients.
So in our world where drugs are becoming increasingly sophisticated
and we’re spending millions of dollars funneling it into research
in order to have some kind of universal a heart failure drug.
We can’t really afford generalizing our conclusions
based on some kind of lackluster model like the ones that I’ve described before.
And then having to go back to the drawing board all over again
when these drugs inevitably don’t work.
So we need something that is a lot more concrete.
We can’t pretend like we live in this vacuum,
because there is a myriad of factors that make us all up as individuals,
our biological sex, our gender, our lifestyle, our diet, our age,
all of these things will inevitably impact the way that we react to disease
and to treatment.
So how does my scientific work fit into the scientific process?
How am I trying to advance these personalized therapies?
Well, first, I meet with patients at the heart failure clinic and I draw
and and I take their blood.
And if this sounds a lot less invasive than the heart biopsy
that we’ve discussed, it’s because it is and it works a lot better.
And so I take this blood and isolate a specific cell type, a blood cell,
which I'm then able to manipulate and reprogram.
What this means is that thanks to
the Nobel Prize-winning work of Dr. Yamanaka and his team
who have discovered these factors,
I’m able to introduce these factors kind of like a script into the cell
and it tells the cell to revert to its most primitive state.
It's kind of like turning back the biological clock
on these cells in order to give us kind of a blank slate.
And these cells are called stem cells.
Now, these stem cells are able to become any cell of our body,
and contrary to heart cells,
they're actually able to replicate as much as we want them to.
And the real advantage to this method is actually the fact
that even though these stem cells are technically a blank slate,
they still contain the DNA and genetic code of each of the patients.
Hence, the patient specificity that we've been wanting all along.
So the next step is to push these stem cells to a new lineage, a new fate.
And of course, I'm in cardiovascular repair medicine,
so I'm excited about heart cells.
And let me tell you, the first time that I did generate these heart cells
was probably the most rewarding moment in my entire research career,
when I saw them beating and culture.
It was an indescribable feeling that I wish I could share with you.
And what we actually ended up having are mini hearts in a dish.
So these mini hearts come from patients and they beat and culture, they behave
a little bit like real hearts,
and we’re able to test different kinds of medications and treatments on them
without going directly to the patients.
So, of course, this avoids the months of trial
and error that negative side effects,
and we actually get a very good picture of what happens on the cellular level
for every single patient line that we generate.
So back to our three patients they are,
currently they have the process that they are subjected to
is kind of like playing a game of darts,
except there’s one problem we’re playing a game of darts but in the dark,
So we have no idea whether when we throw our dart,
it's going to land somewhere until we try.
So for some patients, like Mr. R, it’s gonna work great.
You’re gonna hit the target, you’re gonna you’re gonna
have the right effects for your medicine,
but for other patients your going to hit off-target
or you’re not going to hit the target at all.
And that’s what we want to avoid as much as possible.
With our patient-specific cell model,
we’re still playing a game of darts, right?
We’re still throwing our darts towards the target,
except now we've actually turned on the lights.
And better yet, now we have this fancy laser pointer that we can actually
kind of tell where our dart is going to land.
Quite literally, we can predict at the cellular level
what kind of medicine is going to work for which patient,
which is going to avoid these patients,
the months of trials and tribulations that they were subjected to now.
So why isn't this the new standard nowadays?
Well, there's challenges that come with every single model that we have.
In our case, the challenges are the following.
So the sample size of my study, the production time for these cell lines.
And finally, the inherent limitations that cell lines have as a model.
Now we've discussed these three patients,
and we have patients just like this enrolled in our study,
whose cells, cell lines were trying to generate.
But the fact is, even if we are trying to recruit 250 patients and more,
we might be missing some kind of demographic.
We might be missing some kind of patient type.
Or conversely, we might actually be biased towards one patient type or the other.
So ideally and in an ideal world,
we'd be able to generate cells for everyone.
But that’s actually complicated by the fact that for each patient’s cell line,
it takes about two to three months to generate.
So that's a colossal amount of resources and work that gets put into this.
So now we’re not only juggling the very tangible benefits of having the cell lines
where we can help these patients in a very real concrete way
with the very difficult task of generating these cell lines.
And the truth is, I don't really have an answer
for you today about how we're going to juggle this.
This is part of why we are studying this and we're trying to understand
the differences between each patient.
So we have a better understanding on how to manage these issues.
And finally, drugs, as much as we want them to, are not always targeted.
So for example, if I take a medication for drugs for heart failure,
I hope that it's going to have benefits on my heart, right?
And in the dish, that's exactly what we see.
We can test it in a small little dish on heart cells, but we’re not accounting for.
It’s the different effects throughout the rest of our body,
because drugs have very complicated interactions with other cells
in our body that we’re just starting to understand.
If we're testing medication on a heart in a dish,
we would never know what kind of effect it could have on our brain, our liver,
our reproductive system and so on.
I've got good news for you, though,
because I had told you right?
that the stem cell can generate any cell of our body.
So right now, our lab is really focusing on generating heart cells
because that's kind of the short term goal.
The Holy Grail is to find the next cardiac repair therapy.
But realistically, we could start generating other types of cells
throughout the body in order to test these drug effects and really create
a model that is kind of system wide in a dish.
So that's what I'm hoping for in the near future.
And I would like to say that this project is really in its infancy.
This is a project that matters to me
because like probably many people in this room,
my my I know someone who has had heart disease.
My grandfather actually battled with heart disease for a very long time
before passing away.
And in his case, he wasn't actually he didn't pass away from heart disease.
He passed away from another illness
for which he wasn’t able to get treatment because his heart was so weak.
The point I’m trying to make is that
heart disease may not be the thing that kills you, but it might prevent you
from really living your life to the fullest
and even taking some kind of life-saving strategy in the long term.
So I’m hoping that this kind of model is going to kickstart research
and put this personalized approach at the forefront of drug development,
rather than it being an afterthought,
because we really need to get started on developing these repair therapies
in a good way.
So I hope that we can be patient.
I hope that we can have the patients at the forefront of this process
and we have to start somewhere. So thank you so much.
And I hope that the promise that I give you today
about these personalized therapies
become a reality for all of us at some point in the future.
Thank you.