Establishing DNA as transformation principle

- [Voiceover] So to
review how we got at least

to this video, in 1865,
Mendel first shares his laws

of inheritance.

He observes that there are
these heritable factors,

these discrete heritable factors
that would be passed down

from parent to offspring
according to certain rules.

And he came up with the
laws of inheritance,

law of segregation, law
of independent assortment,

law of dominance.

But as we've said multiple
times, that work at the time

that it was for shared
wasn't taken that seriously.

In fact, a lot of people
didn't pay attention to it

and it wasn't until the early 1900s

that it was rediscovered.

But even when it was first
rediscovered around 1900,

people did not know
what the molecular basis

for these heritable factors
that Mendel talked about,

what the basis of these factors were.

And in 1902, we have the
first really solid theory

for what the molecular basis
for those inheritable factors

actually could be.

This is when Boveri and Sutton come up

and they independently did their work,

but they both came to
the same theory at around

the same time.

They came up with the chromosome theory,

now called the Boveri-Sutton
chromosome theory.

Their work was based on
observing how cells divide,

especially meiosis, and in
seeing how these chromosomes

seem to pair up then segregate
then independently assort

and get passed on to their offspring.

And they said hey, these
chromosomes, on a physical level,

on a molecular level, seem
to be behaving in ways

that are very similar
to the heritable factors

that Mendel talked about.

So it was a very strong theory.

And then we get to 1911 where that theory

gets some more evidence put behind it.

Thomas Hunt Morgan, we talked about it,

he used his fruit flies to
see how that mutant trait

that would pass on from
one generation to another

and the only plausible
explanation that he could

come up with is that
it was being passed on,

on the X sex chromosome.

And him and his team continued
to do more and more work

to establish that chromosomes
indeed seem to be the basis,

the physical location for
these heritable factors

that Mendel first talked about in 1865.

But even Morgan and his team,

when they looked at chromosomes,

a lot of times now when
we think of chromosomes

we think of chromosomes
as being made up of DNA,

and that is true;

but chromosomes are also
made up of other things,

including proteins.

And in the early days,
when people said hey,

it looks like chromosomes
are really the basis

or the location for
these heritable factors,

for these genes.

When people look at these
two different molecules,

they said hey, it's probably
the proteins that are actually

responsible for encoding the
information of inheritance.

Proteins, people knew, were
these complex molecules

that in some ways you could
say encoded information.

Well, at the time, they thought that DNA

were these kind of boring
molecules that surely

this couldn't encode information.

And so the first
evidence, strong evidence,

that DNA is actually where
the genetic information

is encoded doesn't happen
for several more decades.

And we start along that path
with Griffith right over here,

famous for Griffith's experiment,

where he does something
really interesting.

And he by himself, his experiments in 1920

or that he publishes
in 1920 or he actually

he conducts and publishes in 1928,

they aren't responsible
in and of themselves

for establishing DNA to be
the molecule that's actually

the basis of inheritance,
but they start an interesting

path of inquiry where
these gentlemen in 1944

are finally able to establish that DNA

is where these heritable factors

are actually encoded.

So what was Griffith's experiment?

Well, he was studying

strains of bacteria,

and he saw that the same, the two variants

on a certain strain or
two variants of bacteria,

you had the rough strain
and the smooth strain,

if he injected the rough
strain into a mouse,

the mouse lived.

If he injected the smooth
strain into a mouse,

the mouse died.

And it was because the
smooth strain had this

protective coating on it
that made it harder to attack

by the mouses immune system.

So that by itself, well,
that's interesting,

this is the virulent strain,

this is the one that's actually
going to kill the mice.

Now if he took this smooth
strain, the virulent strain

and he heated up so those
bacteria were killed

and then he injected those,
so this is the heat-killed

smooth strain, if he injected
those into the mouse,

the mouse still lived because
those bacteria were dead.

But then he did something
very, very, very interesting.

He took this, the
heat-killed smooth strain,

he took some of that and
he took some of the live

rough strain put together.

Now common sense would
tell you is like okay,

this blue stuff, that's not
going to kill the mouse,

and this killed smooth strain,

that's not going to kill the mouse either.

So if mix it up, that
shouldn't kill the mouse,

but it did kill the mouse,
which was fascinating.

And so he came up with this theory

of a transformation principle.

Even though he killed
the smooth strain here,

there must've been some type of materials,

some type of molecule
that still got transferred

from the dead bacteria
to the live bacteria

and essentially transformed
the live bacteria

into the smooth strain,
allowing them to kill the mouse.

And so he came up with
this idea of some kind of

transformation principle.

And so you can imagine, and
look, it took some time,

over 10 years, now almost two decades,

Avery, McCarty and McLeod said hey,

what is this transformation principle?

Why don't we use Griffith's experiment

and let's keep, instead
of just taking you know

the whole heat-killed smooth strain,

let's try to break it
up into its components

and let's try to isolate
the different components

and keep doing the
experiment until we have

an isolated molecule or
an isolated component

that seems to do the trick.

So they were trying to isolate
the transformation principle.

And they did just as what I described.

They took the heat-killed smooth strain,

they would try to separate the
different constituents out.

You can separate them out physically,

you could use certain
washes that would wash away

certain components.

You could use enzymes that would
destroy certain components.

And eventually, and this
is very meticulous work,

so you can imagine they take the stuff,

the whole dead heat-killed smooth strain

and they start to
separated it out into its

various components.

So that might be one
component right over there,

this is another, let me do
it in these different colors,

this is another component
right over there,

this is another component
right over there.

They're using different
chemical techniques to separate

all of the constituents
that were in that original

heat-killed smooth strain.

And then instead of
running this last phase

of the experiment with the
entire heat killed smooth strain,

they do it with the rough
strain mixed with each

of these components separately.

And then they kept running the experiment

and they would say, hey, look,

when we have this
component right over here

and we tried to run the
experiment, the mouse still lives.

The mouse still lives.

So this one did not
transform the rough strain.

And maybe this one also did
not transform the rough strain.

But then eventually, they
were able to isolate something

that did transform the rough strain.

So the mouse dies,

and so it did transform the rough strain

into the smooth strain.

And so they took this material
and they start applying

all sorts of test to it.

They could look at the
molecular components of it.

And when they looked at
the ratios of nitrogen

and phosphorus, they said
hey, this seems to have

ratios that are consistent with DNA,

which is a molecule
they already knew about.

And it was not ratios that
would've been consistent

with proteins.

They ran chemical tests and said hey,

it doesn't look like there's
a lot of protein in this thing

that we isolated, or even
RNA, which is another molecule

that they new.

Enzymes that would've
degraded proteins or RNA

did not degrade this stuff, but
the enzyme that degraded DNA

did degrade this stuff.

And so they were able to come
up with the idea that DNA

was the transformation principle.

And this is a really,
really, really big deal.

Think about this quest that
we've been going through

for the better part of a hundred years.

Inheritable factors, well,
where are they located?

Hey, it looks like they're
on the chromosomes.

We start having evidence that
they're on the chromosomes.

But chromosomes are made
up of DNA and proteins,

and it wasn't until the start
with Griffith's experiments

and then Avery, McCarty and
McLeod come along and said hey,

let's identify what was it
exactly about the heat-killed

smooth strain

What's the component in it
that actually transformed

the other strain?

And it was DNA.

And what was fascinating
is when you mixed that DNA

from the heat-killed smooth
strain with the rough strain,

that DNA was able to mix in
with the DNA of the rough strain

and allows it to start producing
these smooth protein coats

that allowed it to be more virulent.

So the mouse's immune system
couldn't attack it as well.

So it's really fascinating
on a lot of levels.

You know, the whole
takeaway from this one is

how did we get to DNA
being the important part

of the chromosomes, at
least in terms of encoding

the actual genetic information,

but it's also a cool way to think about

just almost how magical DNA is,

that if you mix it in,
if you mix it in the DNA

of one strain with a live
version of another strain,

you actually might be able
to transform that strain.

In some ways, they were
doing very, very basic

genetic engineering here.