Kind: captions
Language: en
here's what happens when you put your
DNA under a microscope you can extract
some from your mouth just gargle salt
water and mix this with soap and rubbing
alcohol you'll get a gooey mass at the
top this is DNA most of it is yours but
some of it actually comes from bacteria
living in your mouth at 100 times
magnification you'll see these strings
which are coiled up DNA proteins and
debris all clumped together but looking
at them is pretty much useless
I mean even with a million dooll
electron microscope you can't actually
see the genetic code that makes you you
so how do you read DNA DNA DNA evidence
DNA your family secrets you are not the
diseases you haven't been diagnosed with
yet addicting or even diagnosing cancers
the tiny quirks of what makes you
you but for the vast majority of human
history we have not been a
to read it it is completely
illegible all of this might still be
impossible today if not for one man who
took a lot of drugs and stumbled upon a
discovery that unlocked DNA forever also
he was kind of a
jerk in the 1960s as a biochemistry
student at Berkeley Carrie Mullis wasn't
interested in going to his classes he
was too busy taking LSD and lots of it
Mullis didn't take University very
seriously his PhD dissertation was
filled with jokes and the committee
refused to approve it until he quote cut
all the wacko stuff out but LSD fueled
his Ecentric genius sparking all sorts
of interesting ideas it did trickle into
his science so for example he wrote a
letter to the journal Nature which
chronicled the quote entire universe
from the beginning to the end
and they published it um which is
amazing he was like 22 years old they
published that after graduating Mullis
just bummed around for a bit first he
gets a job in A cardiology lab but he's
just kind of so horrified at how many
rats are being killed so he starts
writing fiction he gets a job in a
bakery one day he's working in this
Bakery and this guy Tom white walks in
and it turns out Tom white works at this
company it's a biotech startup called
cedus they start of get to talking and
this guy offers Harry mollus uh he
offers him a job white recommended
mullus to his H high-ups saying hire
this guy mullus he's an excellent
synthetic chemist I knew he was a good
chemist because he'd been synthesizing
hallucinogenic drugs at
Berkeley cedus was one of the first
biotech companies in the world it was
founded in 1971 an exciting time when
scientists were just starting to figure
figure out how to manipulate DNA one of
the most important discoveries was
actually made that year while
researchers at John's Hopkins were
studying the bacteria
Fage the Fage is a virus that hijacks
bacteria by injecting its DNA into the
cell the bacteria is then forced to
create copies of the Fage until it
explodes but the researchers realized
that some bacteria evolve defenses that
make them more resistant to the virus
their defensive molecules would scan the
Fage DNA looking for a specific sequence
and when they found a match they would
cut the DNA turning it into useless
strings scientists called these little
scissor molecules restriction enzymes
and different types of restriction
enzymes cut DNA at different places and
they work on human DNA
too so the researchers extracted the
enzymes to essentially create a toolbox
of nanoscopic syst that would allow them
to cut DNA at
will cedus was trying to use biotech
like this to develop commercial DNA
tests that hospitals could use to
quickly diagnose diseases but at the
time simple DNA tests like this were
impossible say you want to detect sickle
cell disease I mean you could just look
at the blood cells under a microscope
but cedus wanted to prove that they
could do it with a genetic test and for
one of those you would start off with a
sample of
DNA in each of your cells there are 23
pairs of chromosomes and if you zoom
into the tip of the 11th chromosome
you'll find the betag globin Gene this
sequence of adenine thyine guanine and
cytosine nucleotides controls the shape
of your red blood cells and if you
inherit a t instead of an a here from
both of your parents well you're born
with CLE Cel anemia but you can't see
any of this under a microscope so how do
you check these single letter mutations
against DNA that's over 6 billion
letters
long mllly said that this was the
equivalent to reading a license plate on
Interstate 5 in the dark from the moon
but luckily there was a way to do it the
first step is to separate the betaglobin
gene from the rest of the DNA so you can
use restriction enzyme on your sample to
cut the DNA into little pieces all of
different lengths and the CLE cell
mutation will be on one of these ribbons
but how does that help well DNA is
negatively charged so if you place your
cutup sample into a porous material like
a gel and apply a voltage across it the
DNA pieces will flow from the negative
end to the positive end but because
they're all different lengths shorter
pieces of DNA will navigate the gel
pores quicker than longer ones this is
called gel electroforesis and it lets
you separate DNA out by
length its results are consistent enough
that after the DNA is spread across the
gel you can see where different length
strands end up near the start you'll see
DNA strands that are 10,000 base pairs
followed by shorter ones 3,000 1,000 and
so on and because you use specific
restriction enzymes You can predict that
the CLE cell mutation was sliced into a
two ,000 base pair segment so it's in
here and now that we know where the
target DNA is we can move on to step two
checking whether our sample actually has
that mutation or not if you soak the
sample in an alkaline solution or heat
it up to over 90° the hydrogen bonds
between nucleotides will break and the
DNA will
unzip now the two strands will be able
to pair to any other DNA as long as it's
a match a is only pair to T's and G is
only pair to C's
you need a complimentary
sequence scientists could take advantage
of this by synthesizing short pieces of
DNA in a lab these are called probes and
they can be designed to have any
specific
sequence so if the CLE cell mutation is
ctg TG you can create a probe that has
the complimentary sequence GAC a that
will stick to it and because Normal DNA
is supposed to be ctg AG your custom
probe won't be a good
match now the trick is to make these
synthetic probes radioactive and add
them in so after a while your probes
will either pair to the DNA or just keep
floating around and if you wash your
sample any probes that didn't pair will
rinse
off so the final step is to check the
sample for radioactivity you can see
that with CLE cell blood there's a
radioactive signal on the right the
probe found the mutation and stuck to it
but in the case of normal blood there's
no signal none of the probes paired so
there must be no mutation there is also
this other huge signal in both cases
that's because the probes will match to
other parts of the DNA too not just to
the CLE cell region this is why you need
to separate the mutation out using the
gel
first this technique was known as the
southern blot and it worked but there
was a problem it took days or even weeks
every step of it is difficult and every
step of it it's like super inefficient
the matching is inefficient the radio
sensitive paper is really inefficient
and you have these technicians having to
work with radioactive stuff and it
happened in a way that it was so slow
and cumbersome that it wasn't
commercially feasible in any
way cetus wanted a DNA test that could
be done in a day in a single test tube
and they were close they developed a
method that could test for Cle cell
disease in just 7 hours hours but this
new test suffered from a different
problem the signal was just too faint
you could hardly tell whether the sample
had the cleone mutation or not because
it would barely return any
results now Carrie Mullis didn't work on
these Cutting Edge DNA tests his job was
to make those short radioactive bits of
DNA that would be used as probes he
wasn't even doing the interesting part
so he's just making these Snippets
that's his job and it is it is a slow
repetitive extremely boring job so while
he's working there maybe in part because
he is Bored he's just obnoxious he's
like a really annoying person he doesn't
get along with anybody he picks fights
with like receptionists and security
guards and his colleagues he also was a
womanizer so he would be hitting on
people all the time which was at the
same time he was also married there's
one time where he threatened to bring a
gun to work really like like like not
someone would want to work with but one
day they bring in this new machine into
the workplace this machine basically
could synthesize these Snippets all by
itself it's basically doing you know a
month of his work in in in like a day
Mullis he he's like now I both have free
time and I have a lot of these little
DNA Snippets I can sort of play with and
figure out like what can I do with them
and now he doesn't really have a lot of
work to do and and and also people don't
like him at work so he basically starts
taking weekends in mesino County to just
relax as he was driving up to his cabin
on a Friday night in the spring of 1983
Mullis let his mind wander he thought
about that new DNA test and was trying
to think of a way to fix it then a
thought struck him what if instead of
inventing a more powerful telescope to
read a single license plate from the
Moon he just created more of that same
license
plate his mind
raced mullus could see DNA chains
floating all around him blue and pink
images of electric molecules injected
themselves between the mountain and my
eyes he wasn't on LSD but his mind by
then had learned how to get there he
could sit on a DNA molecule watching the
re reactions
unwind see the whole DNA sequence around
the CLE cell mutation was known and
because mullus knew one strand by
complimentarity he knew the other as
well so if he heated up the DNA and
separated the strands he could design
short bits of DNA that would pair to
both strands anywhere on the sequence
these would be his primers then mullus
could use something called DNA
polymerase it's a special protein that
ATT attaches itself to sites like these
where primers are paired to the original
DNA the polymerase basically grabs
nucleotides floating around and extends
the primer and the primer is built as a
perfect complimentary pair to the strand
of DNA it's attached to this creates an
identical copy of the initial double
helix polymerase exists in every cell of
every living thing it is what's
responsible for replicating DNA during
cell division but it will only ever
build out a primer in One Direction it's
kind of like a one-way
Street see each DNA strand starts with a
phosphate molecule this is called the
five Prime end that phosphate is
attached to a sugar molecule called deoy
ribos which holds one of the four
nucleotides and deoxy ribos also
connects to the next phosphate and so
this pattern
repeats but the last deoxy ribos
molecule doesn't have another phosphate
connected to it so it ends with an O
group Instead This is the three prime
end our Street exit the three prime end
on one DNA strand is always connected to
the five Prime end on the
other the second DNA strand always
points the other way and DNA polymerase
needs an O group to attach the next
nucleotide so it always Builds on the
three prime
end but that wasn't a limitation it was
an advantage and Mullis knew exactly how
to use it he could create two primers
that would bind to the DNA before the
CLE cell mutation each on a different
strand pointing at each other and if he
added polymerase along with some spare
nucleotides it would have to extend both
primers toward and over the CLE cell
mutation this would create two separate
DNA segments both with the
mutation a few miles down the road he
had another
Eureka he could just do do these three
steps again unzip the DNA pair the
primers and use polymerase to extend
them he now had four DNA sequences with
the
mutation and he could make that eight
and then 16 32 64 and he realized that
if he repeated this Chain Reaction 30
times he would have over a billion
copies of that specific DNA segment all
with the CLE cell mutation he could
cover the entire Earth with identical
copies of the license
plate and if he designed different
primers he could change the length of
the DNA section that would get
replicated this didn't only work for the
CLE cell mutation as long as you knew
the sequence for any part of any DNA
human plant bacterial you could make
copies of that exact segment and the
copies would grow exponentially like a
nuclear Chain
Reaction mullus has had invented a DNA
photocopier he named it the polymerase
Chain Reaction or PCR for
short immediately he stopped the car and
scribbled his idea on the back of a gas
receipt PCR consumed his thoughts for
the rest of the weekend it was difficult
for me to sleep with DNA bombs exploding
in my brain what if I had not taken LSD
ever would I have invented PCR I don't
know I doubt it I seriously doubt it
Monday morning he burst into the office
at cedus Corp and he pitches his idea
he's like basically look hey I came up
with a DNA xerox machine like I can we
are we are working so hard to read this
tiny tiny thing what if we made a
billion copies of it it would be so much
easier Mullis presented his idea at a
companywide seminar but people started
leaving before he was
done a lot of them are skeptical they've
heard him pitch cockamamy ideas before
the other thing is that they were like
that's so simple it had to have been
tried before and it can't possibly work
like there must be a reason why this is
not the way we're doing this but Mullis
was
undeterred he started his first
experiment in September 1983 trying to
replicate a 400 Bas pair fragment of
human
DNA after months of trying he couldn't
get PCR to work human DNA was just too
complicated so he set his sights on a
smaller fragment of bacterial DNA just
25 base pairs for months he'd separate
the strands attached the primers add the
polymerase hoping to amplify that small
section of bacterial
DNA by the summer of 1984 mullus thought
he had it indisputable proof that PCR
worked but others at cetus weren't
convinced his work was sloppy he didn't
have any controls or do repetition of
his experiments Tom white and Norman
arnheim and other colleague at cetus
said that no one but Carrie believed the
data he showed demonstrated what he said
it did any independent scientist looking
at the data today would come to the same
conclusion Mullis took these comments
personally he constantly argued with his
colleagues about these results and even
started a fist fight at one point he was
losing credibility fast and everyone
wanted him
out but white argued that PCR had
potential so Mullis was given a one-year
probationary period to prove that PCR
could work but he wouldn't be doing it
alone white arnheim and Henry erck
assigned other technicians to develop
PCR along with mullus and from there on
out this group of scientists worked over
time to make PCR a
reality and by Spring 1985 after months
of painstaking trial and error the group
finally cracked it
they had definitive proof that PCR was
possible with it their new CLE cell
diagnostic method worked like a charm
and could be done in under 10
hours but PCR was still just a concept
with a huge problem for each cycle you
needed to raise the temperature to 95° C
to unzip the DNA and then lower it to
around 30° to allow the primers to pair
and the polymerase to extend them
and then you would repeat that cycle
heating back up to 95° the problem was
that the polymerase would get destroyed
when it was heated up it was extracted
from eoli bacteria and eoli can only
survive up to around 50°
C so you would have to stand there and
manually add in more polymerase every
time you cycled the temperature and that
was expensive and timec
consuming you have to do this Loop like
maybe 30 times for a piece of DNA you're
looking at and every time you got to
stop you got to add more polymerase it
was just getting in the way of the
vision and of the of the efficacy this
was like yeah it was adding more time it
was adding more uh difficulty to the
process but it turns out a solution had
been bubbling away in the background for
over 20
years in 1964 a microbiologist named Tom
Brock was visiting Yellowstone National
Park he'd never been before but when he
got to the boiling hot springs
immediately the Vivid Hues of the yellow
and orange water caught his eye are
these colors
bacteria nobody thought that something
could live at higher than 60° C but this
professor Thomas Brock uh this
microbiologist he was like no no no no
no I think not only can things live at
that temperature I think things can live
above a 100 ° C I think things can live
in boiling water Brock set up a lab next
to one of the springs and asked his
undergraduate student Hudson freeze to
tag
along I mean I wasn't even old enough to
drink
and so we would go to the spring and
collect the samples there and then bring
them back to the laboratory for the
analysis so every day oh over about
three or 4 days I would go in and I
would pick up this tube so standard
looking test tube and I would go like
that and I'd flick it just to see if
there was anything growing in
there didn't see anything you know this
is never going to work third day nothing
fourth day oo look at this there's a
little something on the bottom so I
picked up the tube and shook it and this
time there is this deceptic
going like
this and I well that's
interesting so I got a little pipet out
took a little drop put it under a
microscope I still get goosebumps man
I'll tell you I still get
goosebumps I looked at and here are all
these worms just crawling
around I thought my God I'm the first
person in the
world that ever sees this there was a
graduate student in the lab and so this
graduate student said well I think we
ought to call it honi
fanis I mean you do have a great
name and Tom said no no you you can't
name it after a person we're going to
call it thermos aquaticus and the
graduate student and I both looked at
each other hot water I me man that's not
very creative so it meant that if an
organism was going to live out there it
had to have all of its essential enzymes
adapted living at that temperature so it
was clear boiling water is not going to
knock these guys
off but we thought it had no
applications Brock and Hudson published
their findings and stored a culture of
Tac at the American type culture
collection a database that preserves
microbial
samples 16 years later in the spring of
1985 Carrie Mullis stumbled upon their
discovery
he was looking for a polymerase that
could survive the high heat of the PCR
cycle and he had found it at his
suggestion the group isolated the
polymerase out of TAC and tried it in a
PCR test the results were
breathtaking David gelfan the ca
scientist who purified the new
polymerase said it worked like a charm
it worked better than anything we have
ever fantasized the Holy Grail had been
achieved
Not only was Tac able to survive the
high temperature of PCR it thrived in it
these are the results with the old eoli
polymerase you can see that it Amplified
the CLE cell DNA but it Amplified a lot
of the background DNA too so it was
messy that's because primers can
actually attach to DNA even if they
aren't a perfect match they just need a
low enough temperature otherwise the
high kinetic energy peels them off but
with Tac you never had to lower the
temperature below 50° so the primers
would virtually only ever bind to their
target region these were the results
with Tac it completely erased all of the
background
noise you could sort of set it and
forget it and come back you know 30
Cycles later a couple hours later and
and all of a sudden you have a billion
of the thing you're looking for PCR
worked and it worked effortlessly they
could amplify any piece of DNA they
wanted no matter matter how small the
sample cidus realized they had a Golden
Goose but other companies like Perkin
Elmer and Kodak were starting to catch
on to their idea and if anyone else even
briefly mentioned the concept of PCR in
their paper cedus would lose all rights
to the patent so they had to go public
and they had to do it quickly the PCR
group urged Mullis to publish a solo
paper first since PCR was his idea but
Mullis procrastinated afraid they would
lose credit for PCR the rest of the
group was forced to publish an article
on their own PCR research so the first
paper on PCR that came out in Science
magazine in December of 1985 listed
mullus as the fourth
author he was Furious by the time he got
his own paper ready no reputable Journal
wanted it he remarked nature didn't call
me I wasn't one of the good old boys
science rejected it too he claimed the
PCR group stole his work my God they are
going to get away with their little
trick but the group scrambled together
to get mullus the proper
recognition he became the face of PCR
after giving a talk at a microbiology
Symposium in
1986 but it was too late shortly after
still fueled by his anger for the group
mullus left cetus however the work on
PCR continued without him and and after
he leaves they come up with like
basically there are new pc CR machines
that do the whole thing for you um and
and basically these machines are now in
like every every lab that does any kind
of work with DNA
anywhere PCR was a huge
[Music]
success poly Murray's Chain Reaction
test PCR PCR the DNA photocopier has
your remaining blood cancer cells that
other tests can't detect everyone was
using it from DNA cloning and vaccines
to detecting cancer and HIV PCR was
saving lives it completely opened up
everything it revolutionize everything P
PCR PCR could amplify the tiniest sample
of DNA it supercharged forensics Texas
man should be freed from prison because
new DNA evidence does not link him to
the crime hundreds of wrongfully
convicted people were freed and
thousands of criminals were caught
families separated by War could be
reunited we use PCR all the time all the
time everybody in our
Institute scientists even tried to use
PCR on Ancient DNA from insects
fossilized in
Amber sound
familiar like it's it's completely taken
over so much of our world and right at
the center of this takeover Carrie
[Music]
Mullis Dr Carrie Mullis a surfer a
scientist who proved that science can be
fun the world-renowned inventor of
polymerase chain reaction what inspired
you to um invent this it wasn't people
it was uh drugs drug drug drugs any
experience with drugs in 1993 Mullis was
awarded both the Japan prize and the
Nobel Prize in chemistry for his
invention of the polymerase Chain
Reaction method although it wouldn't
have existed without his colleagues
Mullis made PCR his story and his story
only there were a lot of people who were
like he's such a Fame hog like he
completely didn't give any of us credit
I invented PCR after I had invented PCR
and now it's like they bought into his
version of the story um where he he did
this solo whereas there were a lot of
people at cedis Corp who helped him as
erck remarked to Carrie rewriting
history was more important than writing
papers he seems to have viewed PCR as a
means to a
celebrity he he left cus and and as far
as I could tell really stopped being a
scientist when realized I I had in my
hands the thing that would make me
famous asz I knew that night I was going
to get a Nobel Prize for
that he used his publicity to
springboard his eccentric views he
talked about seeing glowing raccoons and
being abducted by aliens he would go
around saying kind of crazy shocking
stuff distrust your fellow man we're
arrogant little bunch of naked Apes he
wrote this book called dancing naked in
the mind field uh which the the blurb on
the book is amazing it's from The
Washington Post and it's like the
strangest guy to ever win the Nobel
prize in
chemistry um he just would do like weird
stuff did you see me eating those
leaves is that a drug he he was an
expert witness in the OJ Simpson trial
he started a company where he would PCR
DNA from famous dead celebrities like
Marilyn Monroe and then he would make
like little trinkets out of them and
sell
them but not all of his ideas were as
harmless he didn't believe in global
warming he didn't believe in the ozone
hole he didn't believe that HIV caused
Aids HIV is not deadly there's not
something called AIDS in the early 200s
HIV denialism in South Africa was at a
high while the country was battling a
crippling AIDS epidemic what we are
facing is a catastrophe which is
undescribable president Tabo Becki was
under the influence of AIDS denialist
does HIV cause AIDS how does a virus
cause a
syndrome it can't and even invited Nobel
Prize winner Carrie Mullis to weigh in
on the
issue under ek's leadership the
government refused to provide adequate
treatment for those affected and more
than 330,000 people
died Carrie Mullis passed away in August
2019 at the age of 74 due to
complications from pneumonia nonetheless
the legacy of PCR lives on just a year
later the method reached perhaps its
most significant use yet as PCR covid
tests helped keep billions of people
safe throughout the
pandemic sometimes he's like he's very
funny and charming and a good
Storyteller but he's also you feel like
he's a very sleazy guy he's like not a
person you'd want to be around he he did
have a sort of a
a like a Sparky mind he was not being
forced by some company to discover
something he was playing it was like
imaginative play he was like I have
these Snippets and what could I do with
them um and to me he invented the
solution and then like a a huge field of
problems emerged to fit but maybe the
real takeaway from Melissa's story is
about automation I mean he discovered
PCR partly because his day-to-day job
was taken over by a machine and this is
a pretty important point because all of
us are maybe staring down the barrel of
a future where machines take over our
jobs especially now with the surge of AI
and generative models and that's pretty
scary but it could also Force us to come
up with bigger more creative ideas just
like it did for car mullus automation
might open our minds to breakthroughs
and discoveries that could change the
world
of course making breakthroughs like PCR
take more than just opportunity you also
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