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  • With the questionwhat is life?”

  • largely addressed at the molecular leveland with companies setting up labs to test how thousands

  • of chemicals affect living thingsand with new technologies like immortalized cell lines

  • and somatic-cellcloning”—humanity could finally cure all disease and live forever

  • Except that didn't happen, becauseas usualthe 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.

  • Likeweeks to months, and it was expensiveand, 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.

  • Andfor a really weird twoin 1998, Mullis wrote an autobiography denying AIDS is a thing.

  • Which is justreally?

  • That's likedenyingpigeons!

  • 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 biologistshopefully

  • 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 representativeworking draftof 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 organismwith

  • a membrane-bound nucleus, like humans!—to have its genome sequenced.

  • Also in 1996, scientists revealed a “mapof 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 itprivately.

  • 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 yearsseven 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

  • flyone 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 foranything!

  • Some DNA serves important regulatory functions, turning coding genes on and off.

  • Some may bejunk.”

  • So in 2003, NHGRI launched ENCODEThe Encyclopedia of DNA Elements Projectin order to understand

  • allfunctional elementsin 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 ofDIY 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 canprofilesomeone

  • 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 itthe 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-calledracesare: 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 thecentury

  • of the gene”: the concept was born, explored, and finally understood to be much more complex

  • than anyone had first thought.

  • Genesaren'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 timewe'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.

  • If you'd like to keep Crash Course free, for everyone, forever you can support the series at Patreon,

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With the questionwhat is life?”

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