With the question “what is life?”
largely addressed at the molecular level—and with
companies setting up labs to test how thousands
of chemicals affect living things—and with
new technologies like immortalized cell lines
and somatic-cell “cloning”—humanity
could finally cure all disease and live forever…
Except that didn’t happen, because—as
usual—the natural world is a lot more complicated
than humans first thought.
Today, we’ll tell the story of the Human
Genome Project.
It’s really cool, you guys!
[Intro Music Plays]
Epistemically, the amount of information contained
within even the smallest organism is simply
mind-boggling.
There is lots and lots of DNA.
Molecular biologists had figured out some
genetic sequences in bacteria and the viruses
that hijack them.
But mapping the human genome?
That seemed like mapping every star in the
universe.
Technologically, scientists in the 1950s and
60s could barely sequence DNA and RNA at all.
One major breakthrough came in 1977, when
British biochemist and double Nobel Prize
winner Frederick Sanger developed a new, reliable
way of decoding DNA that became known as Sanger
sequencing.
Sanger’s method became the standard way
to sequence DNA until the late 1990s, when
“next-gen,” high-throughput sequencers
became available.
It’s complicated, but Sanger sequencing
cleverly works by chopping up an unknown sequence
of DNA, tagging them with four different fluorescent
dyes that bond to the four different nucleic
bases, and then sorting out the segments by
length.
You can repeat the process many times to decode
an entire genome.
One of the main issues is that decoding one
sequence of DNA requires lots of copies of
that sequence.
And copying DNA, up until the 1980s, took
lots of time.
Like… weeks to months, and it was expensive… and, even
then, it didn’t always work!
Enter American biochemist and avid surfer
Kary Mullis.
In 1983, while working at the biotech firm
Cetus in California, Mullis developed polymerase
chain reaction, or PCR.
This was an automated way of taking advantage
of a natural process for copying DNA.
In PCR, cycles of heating and cooling alternate
between melting DNA and copying it using enzymes.
PCR can make billions of copies every hour,
helping scientists quickly replicate strands
of DNA for study.
Mullis and his bosses published a paper on
PCR in 1985, and he went on to win the Nobel
Prize.
You could say Mullis didn’t fit the mold
of a traditional Nobelist.
For one, he admitted to using LSD frequently
in his youth.
And—for a really weird two—in 1998, Mullis
wrote an autobiography denying AIDS is a thing.
Which is just… really?
That’s like “denying” pigeons!
Anyway.
Modern science doesn’t rely on individuals.
It’s a team sport.
And the teams keep getting bigger.
By the late 1980s, some biologists began to
discuss what had seemed impossible a decade
before: completely decoding the human genome.
The stated idea was to understand the different
versions of genes that seem linked to cancers
in order to develop better cancer-fighting
drugs.
Another goal was political: this would be
the Manhattan Project of biology.
The U.S. would fund the future of medicine
and attract the top biologists… hopefully
no bombs, though.
Planning began in 1988, when the U.S. National
Institutes of Health, or NIH, and the Department
of Energy agreed to work together.
And the federal government created the Office,
later the Center, for Human Genome Research.
The Center’s first director was the famous
James Watson.
But he resigned early on,
and physician and geneticist Francis S. Collins
took over.
Collins, by the way, has a rock band called
The Directors!
The Human Genome Project officially began
on October 1st, 1990, with the goal of sequencing
a representative “working draft” of ninety
percent of a human genome—a model blueprint
for a human body.
There was no central hub: instead, many labs
participated, all over the world.
So planning the project took years.
But in 1996, DNA sequencing for the draft
genome finally began at six U.S. universities.
ThoughtBubble, prime us.
Humans are complicated.
So many geneticists began by sequencing related
organisms.
In 1996, an international team finished a
draft sequence of Saccharomyces cerevisiae
, the yeast humans use to make beer, bread,
and biotechnologies.
Although Saccharomyces is a microbe, it was
still the first eukaryotic organism—with
a membrane-bound nucleus, like humans!—to
have its genome sequenced.
Also in 1996, scientists revealed a “map”
of sixteen thousand human genes.
Critics thought HGP would be a gargantuan
waste of money.
But the project was moving much faster than
predicted.
In 1997, the Center became the National Human
Genome Research Institute, or NHGRI.
And then, in 1998, American biotechnologist
J. Craig Venter, entered the competition.
Earlier, Venter had worked at NIH, where he
became an expert in making short synthetic
bits of DNA called "Expressed Sequence Tags."
These were useful for identifying genes…
And Venter and the NIH controversially tried
to patent them.
The U.S. Patent and Trademark Office said
no in 1992, but this battle introduced Venter
to the scientific limelight.
So later, when Venter disagreed with the manner
in which HGP was being managed, he decided
to compete with it—privately.
That’s right: one dude said, I’ll beat
the entire United States government at science!
Venter believed that HGP should switch from
reliable but slow Sanger sequencing to a much
faster but more expensive new method called
shotgun sequencing.!
Sanger sequencing only works on DNA strands
up to ten thousand base pairs, which is very
small.
“Shotgunning” a genome involves fragmenting
it into bits, several times in a row, and
then letting a computer try to piece the blueprint
back together.
Each pass is flawed, but collectively, they
add up to a whole sequence.
Thanks, ThoughtBubble.
Venter wasn’t shy about letting the other
HGP leaders know they were doing their job
wrong.
He officially quit HGP and started a for-profit
company, Celera Genomics, that planned to
use shotgunning and automation to sequence
the human genome in three years—seven years
fasters than HGP.
He would pay for this by holding the sequenced
genes as intellectual property.
That is, he’d continue his decade-long fight
over whether or not human genes can be owned.
This rush to make money from human genes paralleled
the pre-HGP rush to patent cell lines, like
the University of California’s ownership
of Mo, from last episode.
And other companies followed suit.
In 1998, the government of Iceland controversially
licensed the health data of all 275,000 Icelanders
to a private U.S.–Icelandic company called
deCODE Genetics, who were looking for genes
linked to illnesses.
deCODE declared bankruptcy in 2009 and has
since been acquired by different companies.
In early 1999, sequencing of the human genome
at a large scale began, about a decade after
the project started.
This was slow compared to the rapid development
of the atomic bomb, but arguably that’s
like comparing one dangerous apple to billions
and billions of oranges.
And HGP had effects even before it finished.
In 2000, President Clinton signed an Executive
Order to prevent genetic discrimination in
federal workplaces.
The same year, both a public group and Celera
released the genetic sequence of the fruit
fly—one of biology’s rockstar model organisms.
And then, also in 2000, with Venter about
to scoop them, the leaders at the National
Human Genome Research Institute called a truce.
President Clinton, British Prime Minister
Tony Blair, Venter, and Collins collectively
announced the completion of eighty-five percent
of a draft human genome.
Collins and Clinton both invoked religion.
In Collins’ words: “We have caught the
first glimpses of our instruction book, previously
known only to God.”
The complete draft was finished in 2003.
Everybody was a winner.
Private industry had fought the government
to a stalemate and secured serious investment.
The government had spent less than three billion
1991 dollars.
Which, if you think about, really is not much!
And medical researchers, evolutionary biologists,
and bioengineers now had more data than they
knew what to do with!
Within thirteen years, hundreds of scientists
around the world had mapped the roughly three
billion base pairs of DNA that code for a
single human body.
But they understood very little of it.
Originally, they predicted there would be
about one hundred thousands genes, or regions
that code for proteins, in a human genome.
But there are only twenty thousand to twenty-five
thousand.
In fact, most DNA doesn’t “code for”
anything!
Some DNA serves important regulatory functions,
turning coding genes on and off.
Some may be “junk.”
So in 2003, NHGRI launched ENCODE—The Encyclopedia
of DNA Elements Project—in order to understand
all “functional elements” in human DNA.
ENCODE published results in 2012.
On the technology side, the race to map the
human genome drove the price of sequencing
DNA way down.
Sequencing cost continues to fall exponentially:
The first human genome cost three billion
dollars.
Today, sequencing one human genome only costs
about a thousand.
Lots of companies are doing just that.
There are over fifteen hundred biotech companies
in the U.S. today and more than ten thousand
labs that conduct genetic sequencing.
And since 2009, community biology labs have
supported the rise of “DIY bio,” a movement
wherein amateurs can sequence DNA and practice
bioengineering in nonprofit labs.
So what has all this DNA discovery led to?
Immortality?
Flying cats?
I don't... I don't want flying cats.
Sadly, human genetics remain really, really
complicated today.
Medical researchers are still working out
ways to reprogram certain genes to, say, not
give rise to cancer, or to reprogram immune
cells to fight cancer better, without the
need for toxic drugs.
One day, healthcare may be specifically tailored
to your unique genome and we’ll talk about
this vision for personalized medicine in two
episodes.
What HGP and cheap genome sequencing did in
the 1990s and 2000s, however, was change criminal
law and not-change popular understandings
of race.
At first, defense lawyers were suspicious
of DNA evidence.
What if the lab made an error and sent the
wrong person to jail?
But they soon realized that DNA evidence could
be used to exonerate the wrongfully convicted.
Today, DNA is a cornerstone of forensics.
It’s seen as more reliable than fingerprint
evidence.
Of course, some people find it super creepy
that authorities can “profile” someone
using their DNA…
Outside of the courtroom, the Human Genome
Diversity Project, or HGDP, was organized
at Stanford in the 1990s.
Its mission: to collect DNA samples from thousands
of different populations to understand human
diversity.
Its founder, Luca Cavalli-Sforza, was a prominent
geneticist who thought HGDP would fight racism
and celebrate different cultures.
Yet some critics accused HGDP of being racist
by exploiting indigenous people for potential
commercial gain: the World Council of Indigenous
People’s called it “the Vampire Project.”
Ouch.
Recently, genetic ancestry testing has become
commonplace.
These could have highlighted how incredibly
similar all humans are, and how artificial
groupings based on so-called “races” are:
they are the products of imperial census-taking,
not science.
But instead, many ancestry tests reinforce
census race terms.
According to pioneering historian of biology
Evelyn Fox Keller, the twentieth was the “century
of the gene”: the concept was born, explored,
and finally understood to be much more complex
than anyone had first thought.
“Genes” aren’t necessarily the best
or even very good ways of thinking about traits
in the blueprints of organisms.
DNA isn’t a computer language; it’s a
kind of molecule.
And knowing more about it may lead to better
medicine one day, but it’s going to take
a long time.
Next time—we’re headed back to the world
of data.
It’s time for the birth of everyone’s
absolute favoritest place, the Internet!
Crash Course is filmed in the Dr. Cheryl C. Kinney studio in Missoula, MT. And it's made with the help of all these nice people.
And our animation team is Thought Cafe.
Crash Course is a Complexly production. If you want to keep imagining the world complexly with us
check out some of our other channels like Sexplanations, Health Care Triage, and Mental Floss.
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