2- History of Drug Discovery (S1E2)

Welcome back, everybody, for another deep dive.
You know how this works. We take a stack of your
sources and we pull out the most interesting,
the most fascinating knowledge nuggets. Yeah,
it's like a cheat sheet to understanding complex
topics. That's it. That's a great way to put
it. And today's topic, we are time traveling
through the history of drug discovery. OK, buckle
up. We're going from ancient remedies all the
way to modern breakthroughs. the whole journey
right so to start i guess at the beginning humans
have been using natural remedies for millennia
right absolutely but did those ancient cures
actually work or was it all just a bunch of superstitions
that's a great question a lot of people think
that they didn't really work But the truth is
a lot of those ancient remedies were actually
really effective. It wasn't just some placebo
effect our ancestors. They observed the natural
world and they figured out through trial and
error which plants could help alleviate pain,
reduce fever, or even treat infections. I mean
it's incredible to think about those early humans
just experimenting with all these different plants
and trying to figure out which ones could heal
them. It's like a high stakes guessing game.
Oh yeah. Definitely. High stakes for sure. But,
you know, they got pretty good at it over time.
So it wasn't all just random? No, not at all.
I mean, think about it. Many of the drugs that
we use today are actually derived from natural
products that people have been using for centuries.
Oh, wow. So it's like... Traditional knowledge
meets cutting edge science. Exactly. That's fascinating.
Yeah. Can you give us an example, like a modern
drug that has its roots in these ancient remedies?
Oh, sure. Aspirin is a great example. One of
the most widely used medications in the world.
And it's actually derived from willow bark, which
was used by the ancient Egyptians and Greeks
to relieve pain and fever. Wow. So aspirin is
just willow bark. Well, not exactly. It contains
a compound called Salicin, which is what gives
it its pain -relieving properties. Oh, so the
next time I pop an aspirin off, I have to think
about those ancient healers. But how did we go
from just using these plants directly to actually,
like, creating drugs in a lab? Yeah, that's a
big jump, and that's where the concept of what
we call lead drug scaffold structures comes in.
Lead drug scaffold structures. Yeah, so scientists,
they started using natural remedies as a starting
point, a kind of blueprint, if you will, to create
more effective medications. Okay, I'm intrigued.
I need you to break that down a little bit more.
What exactly is a lead drug scaffold structure?
OK, so think of it like this. Imagine a scaffold
that's used in construction. You know, it provides
a basic framework that you can build upon. OK,
yeah. In drug discovery, natural products, they
provide that initial framework or scaffold. OK.
It's like a pre -built foundation that scientists
can then modify and improve upon. So they're
not just copying the plant exactly. Right. They're
taking that basic structure and tweaking it to
make it better. Interesting. They can modify
the molecule to enhance its potency, reduce side
effects, or even target specific areas in the
body. It's like tailoring, but on a molecular
level. Well, that's a good way to put it. Like
taking a rough diamond and cutting it into this
brilliant gem. Exactly. Yeah. And probably one
of the most famous examples of this is the discovery
of penicillin. Oh, penicillin, the wonder drug
that changed everything. Tell me more. Yeah,
so penicillin, it was a total game changer, but
its discovery was a bit of an accident. Really?
Yeah. So Alexander Fleming, the Scottish scientist,
he noticed that a mold was growing in his petri
dish and it was inhibiting the growth of bacteria.
What? Yeah. So that mold was producing penicillin.
And this discovery revolutionized medicine because
now we had a treatment for bacterial infection.
So a little bit of mold led to one of the biggest
medical breakthroughs of all time. That's wild.
Yeah. It is. Science can be messy like that.
Sometimes the biggest breakthroughs come from
the most unexpected places. Yeah, it's true.
So penicillin, is that an example of a lead drug
scaffold structure? Well, penicillin itself is
the drug, but it was the discovery of that mold
and its bacteria fighting properties that led
scientists to further study and develop it into
the drug we know today. Oh, so they took that
mold and turned it into something even more powerful.
Exactly. And it led to the development of so
many other life -saving antibiotics. It's incredible
to think about how far we've come. From ancient
healers chewing on willow bark to scientists
cultivating penicillin in petri dishes. It's
a huge leap. But drug discovery didn't stay stuck
in the mold -in -a -peacher -dish phase forever,
did it? No, of course not. There were more advances
to come. When did things start to get a little
more scientific? Well, the shift towards a more
systematic, science -based approach. It was gradual,
but there were some key milestones that really
propelled the field forward. And advances in
chemistry and biology, those played a huge role.
What kind of advances? Can you give me some examples?
Yeah, so for starters, scientists started to
understand how drugs actually worked on a molecular
level. You know, they began to unravel those
complex interactions between drugs and the body's
machinery. And this allowed them to move beyond
just trial and error and start designing drugs
with specific targets in mind. Oh, so it's not
just like throwing everything at the wall and
seeing what sticks anymore? Not anymore. This
was a big step forward in terms of precision
and efficacy. We could start tailoring drugs
to interact with specific molecules or pathways
in the body. It sounds like they went from shooting
arrows in the dark to using guided missiles.
Exactly. That's a great way to put it. And this
understanding led to the development of what
we call targeted therapies. Targeted therapies?
Yeah, drugs that are designed to interact with
very specific molecules or pathways in the body.
This allows for more effective treatments with
fewer side effects. This is all sounding very
promising. But I know from some of our previous
deep dives that scientific progress is not always
a smooth upward trajectory. Sometimes there are
twists and turns and sometimes those turns lead
to some pretty dark places. Yeah, that's true.
The history of drug discovery, it hasn't always
been sunshine and breakthroughs. Right. There
have been some tragic chapters that really highlight
the importance of, you know, rigorous testing
and regulation. Okay, so let's talk about that.
What kind of tragedies are we talking about,
and how did those tragedies end up shaping the
way that we develop and regulate drugs today?
Well, in the early days of drug development,
there weren't the same kind of stringent regulations
that we have today. Companies could pretty much
market new drugs. without much oversight or testing.
So it was like the Wild West of medicine? Yeah,
you could say that. Yeah. And unfortunately,
sometimes the consequences were devastating.
Like what? Well, one really tragic example is
the case of phalidomide. Oh, yeah, I've heard
of that. Wasn't that the drug that caused birth
defects? Yeah, that's right. It was marketed
as a sedative and an anti -nausea medication
and it was prescribed to pregnant women to help
with morning sickness. Oh, it's heartbreaking
to think that a drug that was meant to help expecting
mothers could end up having such horrific effects.
It was a terrible tragedy. Thousands of babies
were born with severe deformities because of
exposure to thalidomide. It was a real wake -up
call for the medical community and for the public.
Yeah. It really highlighted just how badly we
needed stricter drug regulations. It's hard to
imagine something like that happening today.
How did that thalidomide tragedy change how we
approach drug development and regulation now?
Well, it served as a catalyst for some major
reforms in drug safety regulations around the
world. In the United States, it led to a strengthening
of the FDA's authority. The Food and Drug Administration.
Yeah, exactly. The FDA was given much greater
power to oversee drug testing and approval. So
now, new medications, they have to undergo rigorous
clinical trials to demonstrate both their safety
and their efficacy before they can be marketed
to the public. So it went from like buyer beware
to safety first. Yeah, you could say that the
thaldimide tragedy made it very clear that a
system based solely on trust and a lack of oversight
was not going to work. Right. It just wasn't
adequate to protect public health. We needed
a new era of scientific rigor and accountability
in drug development. That makes sense. It's sobering
to think that it took such a horrific event to
bring about these much needed changes. True.
But ultimately, it led to a system that prioritizes
patient safety above all else. Absolutely. The
philatomide disaster was a painful lesson, but
it fundamentally changed the way we approach
drug development and regulation. And now we have
a system that's far more robust and focused on
protecting the well -being of patients. So we've
talked about, you know, that historical evolution
of drug discovery from those early trial and
error approaches to the more science -based methods
and then implementing those really strict regulations.
But there's one piece of the puzzle that I'm
still a little curious about. You mentioned something
called in vitro in vivo correlation earlier.
Can you explain what that means and why it's
so important in modern drug development? Sure,
in vitro in vivo correlation or IV IVC as it's
often called refers to the relationship between
how a drug behaves in a controlled laboratory
setting in vitro and how it behaves within a
living organism in vivo. Okay, so it's like trying
to bridge that gap between the lab and the real
world. But why is that so important? Why not
just test drugs directly in living organisms
from the beginning? Well, testing in living organisms
is essential. But in vitro studies, they provide
a really crucial foundation for drug development.
They allow scientists to screen a large number
of potential drug candidates very quickly and
efficiently. And it helps to identify those promising
leads before moving on to the more complex and
expensive in vivo studies. So it's kind of like
a preliminary screening process to weed out the
duds and just focus on the most promising candidates.
Exactly. In vitro studies, let researchers assess
a drug's basic properties, like its solu - ability
stability, and how it interacts with specific
target molecules. And this information helps
to guide the selection of drug candidates that
are most likely to be effective and safe in living
organisms. OK, so it's a strategic approach,
but it's not always a perfect prediction, right?
Just because a drug behaves a certain way in
a test tube doesn't mean it's going to behave
the same way in a more complex living system.
You're right. That's where the correlation part
of IVIVC comes in. The goal is to establish a
strong relationship between that in vitro data
and the in vivo results. Ideally, what we observe
in the lab should accurately predict how the
drug will behave in a living organism. It makes
sense, but I imagine it's pretty challenging
to create that kind of seamless connection. The
human body is incredibly complex. It definitely
is. There are so many factors that can influence
a drug's behavior within the botter. Things like
pH levels, enzyme activity, interactions with
other medications, and even just individual variations
in metabolism can all play a role. So it's not
just about replicating the exact chemical conditions
of the body in a test tube. Right. It's about
understanding all of those complex interactions
and how they might affect the drug's performance.
Wow. So IVIVC is about more than just the science.
It's about understanding the whole picture. Absolutely.
And that's why it's such an active area of research.
Scientists are constantly developing more sophisticated
in vitro models that can better mimic the complex
environment of the human body. Wow. And they're
using advanced mathematical modeling techniques
to try to predict in vivo behavior based on that
in vitro data. It's almost like they're trying
to build a virtual human in the lab to test these
drugs on. In a way, yes. They're striving to
create in vitro systems that are as predictive
as possible of what will happen in a living organism.
And this helps to reduce the reliance on animal
testing, and it can accelerate the drug development
process, ultimately bringing safe and effective
medications to patients faster. Wow. It's incredible
to see how far we've come in our ability to understand
and predict those complex interactions between
drugs and the human body. But even with all of
these advances, I'm guessing there's still some
challenges and limitations when it comes to IVIV.
Of course. The human body is so incredibly complex
and we're still unraveling many of its mysteries.
There are always going to be factors that are
difficult to predict or to replicate perfectly
in a laboratory setting. But IVIVC, it remains
a really powerful tool in drug development. It
helps to streamline the process, reduce costs,
and ultimately improve patient outcomes. Absolutely.
Yeah. So we've covered a lot of ground today,
from ancient remedies to modern drug development
and the crucial role of in vitro in vivo correlation.
Yeah. But I'm curious. How do all these pieces
fit together? How do scientists actually use
all of this knowledge to develop and test new
drugs? That's where the biopharmaceutics classification
system, or BCS, comes in. It's a framework that
helps scientists categorize drugs based on their
solubility and permeability. Basically, how easily
they dissolve and get absorbed into the bloodstream.
OK, so it's like a sorting system for medications.
Yeah. But why is that so important? Why does
it matter how soluble or permeable a drug is?
It matters a lot because these properties can
really affect a drug's bioavailability. That
is how much of the drug actually reaches the
bloodstream and becomes active. A drug with poor
solubility might not dissolve properly in the
digestive system, meaning a smaller amount of
the drug will actually be absorbed and able to
do its job. So it's like having a fancy sports
car but only being able to drive it at five miles
per hour. Exactly. It's not reaching its full
potential. And the BCS helps scientists to anticipate
these potential roadblocks. early on in the drug
development process. By understanding a drug's
solubility and permeability, they can design
formulations and delivery methods that optimize
its absorption and effectiveness. Makes sense.
So how does this BCS system actually work? How
are drugs categorized? Well, the BCS categorizes
drugs into four main classes. Class one, high
solubility, high permeability. These are the
superstars. They dissolve easily and get absorbed
quickly, making them relatively straightforward
to formulate. Then we have class two, low solubility,
high permeability. These drugs are good at crossing
membranes once they're dissolved, but dissolving
them in the first place is the challenge. Particle
size and formulation become really crucial for
these drugs. So it's all about getting them to
dissolve first. Exactly. Then there's class three,
high solubility, low permeability. These drugs
dissolve readily, but they struggle to cross
those membrane barriers. and get into the bloodstream.
So scientists often focus on enhancing permeability
for these drugs. Interesting. And the last class.
Class four, low solubility, low permeability.
These are the underdogs, difficult to dissolve
and struggle to get absorbed. They present the
biggest challenge for drug developers. Sounds
like a real balancing act. Scientists need to
consider both solubility and permeability when
designing and testing new medications. They do,
and the BCS helps guide those decisions, ensuring
that drugs are formulated and administered in
a way that maximizes their chances of success.
Okay, so let's bring this back to our listeners.
Why should they care about the BCS? How does
this system actually impact them as patients?
Well, for starters, the BCS can play a role in
generic drug approvals. Generic drug manufacturers
need to demonstrate that their version of a drug
is bioequivalent to the brand name version, meaning
it gets absorbed into the bloodstream at a similar
rate and extent. And for drugs in those less
desirable categories like class two or class
four, even slight variations in manufacturing
can impact their bioavailability. So taking a
generic version of a class two drug could potentially
lead to different results. compared to the brand
name version. It's a possibility, although regulatory
agencies like the FDA have very strict standards
in place to try and minimize those variations.
But it's something to be aware of, especially
if you're taking a medication where consistent
absorption is really critical. That's good information
to have. It sounds like the BCS is kind of a
behind the scenes player in ensuring that medications
are safe and effective. Exactly. It's one of
those unsung heroes of the pharmaceutical world.
It's a framework that helps guide drug development
and testing, and ultimately it leads to better
treatments for patients. Well, this has been
an incredible journey. We've gone from ancient
remedies and trial and error to modern drug development
with all its sophisticated laboratory techniques
and the intricate dance between solubility and
permeability. I think we've given our listeners
a lot to think about today. I agree. The history
of drug discovery, it's a testament to human
ingenuity and our unwavering pursuit of better
health. And as we continue to unravel the complexities
of the human body, we can expect even more groundbreaking
discoveries and innovative treatments in the
years to come. Well said. And a big thank you
to our listeners for joining us on this deep
dive into the fascinating world of drug discovery.
Until next time, keep exploring, keep asking
questions, and keep those brains buzzing. Yeah,
it was, you know, a horrible tragedy. Thousands
of babies were born with really severe deformities,
all because of exposure to thalidomide. And it
was a huge wake -up call for everyone in the
medical community and for the public. It showed
just how badly we needed stricter regulations
for drug development. It is hard to imagine something
like that happening today. So how did that thalidomide
tragedy change how we approach drug development
and regulation? Well, it was a catalyst for some
major reforms in drug safety regulations all
over the world. OK. And in the US, it led to
the strengthening of the FDA's authority. The
Food and Drug Administration. Yes. The FDA was
given a lot more power to oversee the testing
and approval of new drugs. So now new medications,
they have to go through really rigorous clinical
trials to demonstrate both their safety and how
well they work before they can be made available
to the public. So it was a big shift from buyer
beware to safety first. Yeah, you could say that.
The thalidomide tragedy made it really clear
that we couldn't rely on a system that was based
only on trust without any real oversight. It
just wasn't enough to protect public health.
We needed a new era of scientific rigor and accountability
when it came to developing new drugs. That makes
sense. It's kind of sobering to think that it
took such a horrific event to bring about these
changes. But ultimately, it led to a system that
really puts patient safety above all else. That's
right. The thalidomide disaster was definitely
a painful lesson, but it fundamentally changed
how we approach drug development and regulation.
Yeah. And now we have a system that is much more
robust and focused on protecting the well -being
of patients. So we've talked about that whole
evolution of drug discovery from the early trial
and error approaches to the more science -based
methods and then implementing these strict regulations.
But there's one piece of the puzzle that I'm
still kind of curious about. You mentioned earlier
something called in vitro, in vivo correlation.
Could you explain what that is and why it's important
in modern drug development? Sure. So in vitro,
in vivo correlation or IVIVC, as it's often called,
refers to the relationship between how a drug
behaves in a very controlled laboratory setting,
which we call in vitro, and how it behaves in
a living organism, which we call in vivo. OK,
so it's like trying to bridge that gap between
the lab and the real world. Why is that so important?
Why not just test drugs directly in living organisms
right from the start? Well, testing in living
organisms is essential, of course. But in vitro
studies, they provide a really important foundation
for drug development. They allow scientists to
screen a large number of potential drug candidates
quickly and efficiently. OK. And that helps to
identify those promising leads before having
to move on to the more complex and expensive
in vivo studies. So it's like a preliminary screening
process to weed out the duds and focus on the
most promising candidates. Exactly. In vitro
studies, let researchers assess a drug's basic
properties, like its solubility, its stability,
and how it interacts with specific target molecules.
And that information really helps to guide the
selection of drug candidates that are most likely
to be both effective and safe in living organisms.
So it's a very strategic approach. Yeah. But
I'm guessing it's not a perfect prediction, is
it? Just because a drug behaves a certain way
in a test tube doesn't necessarily mean it's
going to behave the same way in a complex living
system. That's true. And that's where the correlation
part of IVIBC comes in. The goal is to try to
establish a strong relationship between the data
that we get from those in vitro experiments and
the results we see in vivo. Ideally, what we
see in the lab should accurately predict how
the drug is going to behave in a living organism.
That makes sense. but I imagine it can be pretty
challenging to create that kind of seamless connection.
You know, the human body is incredibly complex.
Oh, it is. There are so many factors that can
influence how a drug behaves inside the body.
Things like pH levels, enzyme activity interactions
with other medications, even just variations
in a person's metabolism can all play a role.
So it's not as simple as just recreating the
exact same chemical conditions of the body in
a test tube? No, not at all. It's about understanding
those really complex interactions and how they
might affect how well the drug performs. So IVIVC,
it's about more than just the science. It's about
seeing the bigger picture. Yeah, exactly. And
that's why it's a really active area of research.
Scientists are constantly developing more sophisticated
in vitro models that can better mimic the very
complex environment of the human body. Wow. And
they're using advanced mathematical modeling
techniques to try to predict that in vivo behavior
based on the in vitro data that they collect.
So it's almost like they're trying to build a
virtual human in the lab. to test these new drugs
on? In a way, yes. The goal is to create in vitro
systems that are as predictive as possible so
we can get a good sense of what will happen in
a living organism. And this has some really important
implications. It helps reduce the need for animal
testing and it can speed up the drug development
process. So ultimately, it helps us bring safe
and effective medications to patients more quickly.
It's amazing to see just how far we've come in
our ability to understand and predict these complex
interactions between drugs and the human body.
But even with all of these advances, are there
still challenges and limitations when it comes
to IVIVC? Oh, of course. The human body is just
so incredibly complex and we're still working
to unlock many of its secrets. So there are always
going to be factors that are hard to predict
or to perfectly replicate in the lab. However,
IVIVC remains a really powerful tool in drug
development. It helps to streamline the process,
reduce costs, and ultimately improve patient
outcomes. Hashtag TTS, the deep dive episode
2025 0305 part three of three. Okay. So we've
covered a lot of ground from ancient remedies
to modern drug development and that crucial role
of in vitro. in vivo correlation. But I'm curious,
how do all of these pieces actually fit together?
How do scientists use all of this knowledge to
develop and test new drugs? Well, that's where
the biopharmaceutics classification system, or
BCS, comes in. BCS. Yeah, it's a framework that
helps scientists to categorize drugs based on
their solubility and permeability, basically
how easily they dissolve and get absorbed into
the bloodstream. OK, so it's like a sorting system
for medications. But why is that so important?
Why does it matter how soluble or permeable a
drug is? It matters a lot because those properties
can significantly affect a drug's bioavailability.
That is how much of the drug actually reaches
the bloodstream and becomes active. So a drug
with poor solubility might not dissolve very
well in the digestive system, which means that
a smaller amount of the drug will actually be
absorbed and be able to do its job. So it's like
having a fancy sports car, but you can only drive
it at five miles per hour. Exactly. It's not
reaching its full potential. And the BCS helps
scientists to kind of anticipate these potential
roadblocks early on in the drug development process.
By understanding a drug's solubility and permeability,
they can design for formulations and delivery
methods that optimize its absorption and effectiveness.
That makes sense. So how does this BCS system
actually work? How are drugs categorized? So
the BCS categorizes drugs into four main classes.
We have class one, high solubility, high permeability.
These are the superstars. They dissolve easily.
They get absorbed quickly, making them pretty
straightforward to formulate. OK. Then you've
got class two, low solubility, high permeability.
These drugs are really good at crossing membranes
once they're dissolved. But getting them to dissolve
in the first place can be a challenge. So particle
size and formulation, those become really crucial
for these drugs. So it's all about getting them
to dissolve first. Exactly. Then there's class
three, high solubility, low permeability. These
drugs dissolve really well, but they struggle
to cross those membrane barriers and get into
the bloodstream. So for these drugs, scientists
often focus on trying to enhance their permeability.
Interesting. What about the last class? Class
four, low solubility, low permeability. These
are the underdogs. Difficult to dissolve and
they struggle to get absorbed. Presenting kind
of the biggest challenge for drug developers.
So it sounds like a real balancing act. Scientists
need to consider both the solubility and permeability
when designing and testing new medications. Absolutely,
and the BCS is there to help guide those decisions,
making sure that drugs are formulated and administered
in a way that maximizes their chances of success.
Okay, so let's bring this back to our listeners.
Why should they care about this BCS? How does
it impact them as patients? Well, for one thing,
the BCS plays a role in the approval process
for generic drugs. Generic drug manufacturers,
they need to demonstrate that their version of
a drug is bioequivalent to the brand name version.
You know, meaning that it gets absorbed into
the bloodstream at a similar rate and extent.
And for drugs that fall into those less desirable
categories, like the class 2 or class 4, even
small variations in the manufacturing process
can actually have an impact on their bioavailability.
So taking a generic version of, let's say, a
class 2 drug could potentially lead to different
results compared to taking the brand name version.
It's possible, although, you know, regulatory
agencies like the FDA, they have very strict
standards in place to try to minimize those kinds
of variations, but it's something to be aware
of, especially if you're taking a medication
where that consistent absorption is really important.
That is good information to have. It sounds like
the BCS is kind of this behind the scenes player
in making sure that our medications are safe
and effective. Exactly. It's one of those unsung
heroes of the pharmaceutical world. It's a framework
that helps guide drug development and testing,
and ultimately it leads to better treatments
for patients. Well, this has been such an incredible
journey. We started with ancient remedies and
trial and error, and now we're talking about
modern drug development with all of its sophisticated
lab techniques and this intricate dance between
solubility and permeability. I think I've given
our listeners a lot to think about today. I agree.
The history of drug discovery is a testament
to human ingenuity and our never -ending pursuit
of better health. And as we continue to learn
more about the complexities of the human body,
I think we can expect even more groundbreaking
discoveries and innovative treatments in the
years to come. That's a great point. And a big
thank you to our listeners for joining us on
this deep dive into the fascinating world of
drug discovery. Until next time, keep exploring,
keep asking questions, and keep those brains
buzzing.