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ERIC S. LANDER: What are we going to do in this course if we're not going
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to study the whole diversity of life, and we're not going to study all of
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evolution, and we're not going to study all the details of cell biology?
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What we're going to do in this course is, we are going to study the
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fundamental principles, and we are going to study the intellectual
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unification of biology.
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Fundamental principles and the intellectual unification of biology--
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all of it is essentially the story of about the last 100 years.
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It's about the last 100 years.
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And it can be summarized in a diagram that I'm going to use again, and
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again, and again.
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And it's the coat of arms of this course.
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And you will see the diagram essentially every lecture, and it's
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going to be a you are here kind of diagram.
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At any given point of the course, you're going to know where we are.
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And by the time we're done, you'll truly understand the
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meaning of this diagram.
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We want to understand biological function--
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how biology does things, how the butterfly flies this beautiful morphal
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butterfly flapping its wings, flying.
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How does it do it?
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How does it make those wings fly?
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How do the muscles work, the nerves work?
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How does any of that happen?
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And then the butterfly reproduces and produces more butterflies.
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How does that happen?
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We want to understand biological function.
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Well, for a very long time, the ancient Greeks used to study
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biological function by sitting around thinking hard about it.
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It was a long tradition, a philosophical tradition of sitting
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around thinking about things.
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Aristotle, I believe, was convinced that sex determination--
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whether the baby was going to be a boy or girl--
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had to do with whether or not the couple conceived the child in a north
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wind or a south wind.
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There was no experimental data to support this.
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There was a long period of time that people noticed that brains are hot,
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heads are hot.
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And they radiated a lot of heat.
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And it was held that the brain was a radiator, a device
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for dissipating heat.
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It may be in many cases, but we'd like to think that it has other, more
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important functions.
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These are observational things without testing.
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Now, don't get me wrong, observation is incredibly important.
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The invention of the microscope and the ability to see cells, see
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structures within cells, taught us tremendous amounts.
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So I'm not dissing the power of observational biology.
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But until we had analytical biology, the ability to test ideas by
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experiment, we really couldn't know that we were right.
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And we could be as wrong as easily as we were right about things.
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The 20th century largely opens with two ways to study biology, two ways to
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study biology.
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One of them is called biochemistry.
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Biochemistry is the idea that we can understand life by grinding it up,
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fractionating it into little pieces, and studying individual components.
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Biochemistry is the study of individual components purified away
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from the rest of life--
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one component away from the rest.
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And it involves purifying that component away from
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the rest, very often.
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So how would a biochemist study the morphal butterfly flapping its wings
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and trying to understand that?
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The biochemist would start by taking the butterfly, putting it into the
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blender, and homogenizing it in some way.
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By the way, I'm a geneticist not a biochemist, so I get
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to say these things.
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The biochemist would grind it up and look for proteins or components that
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might be able to slide by each other and act like muscles.
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And the biochemist would be happy when she was able to take some components
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out of pureed butterfly and show that they could in fact slide back and
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forth without the whole rest of the butterfly.
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That's biochemistry.
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It's pretty powerful, though, because if you can actually make something
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work without the whole rest of the butterfly, it's impressive.
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You really know that you've got the cause of it.
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And very often the most interesting things that the biochemists would
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isolate were molecules called proteins.
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Now, an utterly complimentary point of view also started essentially at the
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exact same moment at the beginning of the 20th century.
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And that was genetics.
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Geneticists do exactly the opposite.
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If biochemists study one component away from the rest of the organism,
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what a geneticist does, is a geneticist studies an organism minus
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one component--
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the whole organism takeaway one component.
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Now, how do I take away one component?
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It's a mutant, a mutant organism, an organism with exactly one defect.
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Something's wrong that's broken exactly one component, but you
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otherwise have the whole organism there and functioning.
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So here what we have is the organism minus one component,
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that is to say mutants.
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And geneticists didn't know what was missing.
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Geneticists had no idea what was missing.
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And when you don't know, you give it a name, because it
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makes you feel better.
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And what they called the thing that was missing, the thing that gave rise
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to this trait, this thing, they called it a gene.
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Gene, like generating, like genesis, beginning, making--
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a gene.
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For 50 years, the first half of the 20th century, biochemists did
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biochemistry.
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Geneticists did genetics.
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Two complimentary ways of studying life.
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They actually had almost nothing to say to each other.
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They had nothing to say to each other, because you see, the geneticists were
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studying this organism minus something, but they couldn't put their
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hands on the something.
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They couldn't purify the something.
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They couldn't know what the thing was, but they could study the rules of
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inheritance of it.
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They could study the diverse things that could happen
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when you made mutants.
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The biochemist, they can grind up things and purify it, but they were
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studying these single components in the test tube away from the rest of
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the organism.
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And they couldn't really tell you how it worked together
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with the whole organism.
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Yeah, these two things could slide by, and maybe that was
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the basis of muscles.
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But how would you know?
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The geneticist would look for a butterfly that couldn't fly, maybe
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look for 20 different kinds of butterflies that couldn't fly, start
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crossing them together and asking, how many different ways can a butterfly
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have a mutation that prevents it from flying?
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Well, some mutations might cause no wings, some no muscles.
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Some have muscles, but the muscles don't work.
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But the two sides couldn't talk to each other.
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And yet we knew somehow these things were connected.
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The first great intellectual unification occurred at the middle of
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the 20th century.
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And it was the recognition that there was an intimate link
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between genes and proteins.
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And that intimate link between genes and proteins is what we call molecular
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biology, the study of molecular biology.
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And it is the genes, which it's no surprise to you.
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I'm not going to be able to keep suspense up on this.
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Genes are DNA.
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They encode the instructions for the proteins.
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But just because you learned that in kindergarten and everybody knows that
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the DNA encodes proteins and things like that, you shouldn't find that to
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be any less amazing.
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And you shouldn't lose track of what a stunning intellectual unification
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there was when genetics and biochemistry turned out to be flip
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sides of the same thing.
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The thing that was missing encoded those single components that were
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being studied.
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And the DNA was read out into RNA, an intermediate molecule which then was
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used to produce proteins.
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And that intellectual unification precedes Crick and Watson.
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But Crick and Watson with the double helix provided such an amazing
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understanding of how it is that DNA might encode those proteins.
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And the next decade or two are figuring out how the DNA
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encodes those proteins.
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That got us to about 3/4 of the way through the 20th century.
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And folks were so pleased with themselves.
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They said, ahh, we have it.
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We know the secret of life.
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Let's stop and do something else.
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But as always happens, young people come along.
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And the young people said, you know, you old guys, you're so pleased you
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discovered the secret of life--
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genes encode proteins.
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You can't actually read a single gene.
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It's all theoretical.
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You've proven it.
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There's no doubt that that's the case--
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DNA encodes the RNA and encodes the proteins.
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But you haven't read a single gene.
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Isn't that pathetic?
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And the older generation said, well, you know, we've got the basic
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principle down.
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And it's not possible to purify single genes from other genes, because
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they're all made out of DNA, and they all look the same.
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Well, in the 1970s came an amazing revolution where it became possible to
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purify single genes away from each other and to work with single genes
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and read single genes, reproduce those genes and sequence those genes and
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change those genes, at least in a test tube.
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And that's what's called recombinant DNA.
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Recombinant DNA took what was an utterly theoretical picture, a
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beautiful theoretical understanding, and it made it operational.
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It made it practical.
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It made it possible to then say, oh, I can actually read a gene and figure
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out what protein it's encoding.
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Oh, I can take a protein and figure out what gene encodes it.
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Oh, I might be able to knock out a gene and see
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what function it subserves.
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I can actually move around this diagram, and this diagram now becomes
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a diagram that I can traverse around and around and around.
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And that got us to the mid 1980s.
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In the mid 1980s, people were so pleased with themselves.
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They said, hey, we can now do this.
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We can operationally read out genes and all that.
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And of course, the young people came along and said, that's great.
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You're all pleased with yourselves.
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But you know what?
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There are all these human diseases--
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cystic fibrosis, and Huntington's disease, and this, and that, and the
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other thing.
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Can you find the genes for any of that?
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Well, no, not really.
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If we knew what the protein was, we could find the gene.
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And if we knew what the gene was, we could find the protein.
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But as it happens, we don't know either and not much we
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can do about that.
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And the problem was that people were studying genes one at a time.
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All of the genes--
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we call it the genome--
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was very big, so big, that to people in the mid 1980s, it might as well
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have been infinite.
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And people said, we're never going to really get to it.
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Or some time in the next century, we might get the whole thing.
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We've got to study single components, single genes.
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But an idea began getting going in the mid 1980s, which is about when I got
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involved in biology, that said, why not?
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Why can't we look at the whole thing?
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Why can't we take a systematic look at the entire genome, all the genes
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simultaneously?
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And it wasn't just a question of big scale.
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It's that when you look at the entirety of a picture, you see
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different things.
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And so it was born, standing outside--
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I'll draw here this eye looking down--
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genomics, global views, systematic views, of all of the
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genes, all of the proteins.
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And you just think about it.
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If I want to study the Earth, I can go walking around on the ground and I can
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see Manhattan.
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I might go walking around and stumble onto the Grand Canyon or the
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Mississippi.
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But how do I put those pieces together unless I can get the entire Earth?
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You know, it's like in the 1300s when people might know their little local
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neighborhood but had no idea what the whole Earth was like.
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And it turns out pretty amazing things happen.
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When you look at the entire Earth, you realize that South America and Africa
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kind of fit together.
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And boy, it turns out to be continental drift.
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And you learn amazing things at scale you don't otherwise learn.
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You learn about large formations.
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You can take an unbiased look.
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I can find the deepest deep and the highest high and all sorts of
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properties and things like that.
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And that's what we've begun to do, because in the mid 1980s,
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people began a process.
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The biggest aspect of it was called the Human Genome Project.
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And I was very much involved together with other people in the Human Genome
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Project to try to read out all the information in the human genome.
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And it was certifiably nuts to try to do that in the mid 1980s.
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But people put together some plans.
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They were pretty sketchy plans if you ask me.
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But somehow people convinced the United States Congress that it was all
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going to work.
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Please don't ask for details.
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And the Congress being very sensible, said, we understand.
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If the scientific community thinks this is really going to work and is
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prepared to put its neck on the line, we'll back you for a while.
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We'd like to see results along the way.
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And a lot of young people poured into the field and began working on a Human
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Genome Project.
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And by 2000, 2001, we had a rough sequence of the whole human genome.
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By 2003, we had a finished sequence of the whole human genome.
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That's about 10 years ago.
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For about 10 years, we've had a finished sequence of
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that whole human genome.
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And now we can stand back, and we can get the genes associated with
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particular diseases.
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And we can move around this diagram not just for individual pieces but for
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the whole picture.
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And we see the whole thing.
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And we were so pleased with ourselves, because we just had the entire world
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work together to get one human genome.
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It cost about $3 billion, which over 10 or 15 years isn't that all much.
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It turns out that's by $300 million a year.
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It's not terrible.
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In terms of The National Institutes of Health budget, it's 100
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times larger than that.
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It was only about 1% of the National Institutes of Health budget
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that went to it.
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And of course it was done not just in the United States, but it was also the
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United Kingdom, and France, and Germany, and Japan, and China working
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together on this whole thing.
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But we were so pleased with ourselves.
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But of course, what if we wanted a second human genome?
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Is that another $3 billion?
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We've gotten pretty good.
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It was down to $300 million.
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But that was still pretty expensive.
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What has happened in the last decade?
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It's every bit as mind blowing as all the previous decades.
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What's happened in the last decade, is the cost of sequencing has fallen by
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about a million fold.
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Whereas it was once $3 billion, it's now $3,000, $4,000, or $5,000 to
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sequence entire human genome.
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There's nothing that beats that that I know of in human history.
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The folks who brag about Moore's Law on computers and how the cost of
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electronics of storage and processing fall, and fall, and fall
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exponentially.
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This is much faster than that.
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It's gone much faster than Moore's law-- million fold in the course of a
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decade or so.
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And suddenly, it means that today it's possible not to stop at sequencing
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single genomes, but thousands of genomes, 10s of thousands of genomes.
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And just in the past several years I've been teaching this course, I keep
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telling the class how many genomes have gotten sequenced.
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And I'll tell you when we get to the relevant part of the course, but it's
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going to be a very large number of how many genomes have
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gotten sequenced already.
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And we're learning all sorts of things.
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Whereas about the time you guys were born, I'll subtract the number of
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genetic diseases that people really knew about was measured in the dozens.
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Today, it's measured in the--
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about 5,000 genetic diseases for which we have genes associated with them.
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Pretty remarkable, and it's going faster and faster and faster.
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So what I want you to take away more than anything is that this is a course
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about something that is changing as we're teaching it.
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The reason I love teaching introductory biology is because you
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need to know about this.
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You need to do this idea of the secret of life, because it's going to be
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affecting everything we do.
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It's going to be in the newspapers.
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There will be unpredictable things that are happening
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every week, every month.
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And you need the fundamentals to understand what that's about.
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This is understandable stuff.
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It's amazing stuff.
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We are going to come back again, and again, and again to this diagram--
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genetics, biochemistry, and molecular biology that connects them, the
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recombinant DNA, the genomics, and then the amazing things that are going
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on right now, the ideas that are even unimaginable.
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Writing software for cells and DNA, changing what cells do.
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There's all sorts of folks who are saying, oh, you guys are all so
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pleased with yourself.
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But there's so much more we could be doing.
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And there are people here at MIT and people all over the world thinking
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about what the next revolution is about.
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Anyway, that's what the course is about.
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It's what it's not about.
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There's things we're not going to be able to do, and the things we are
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going to be able to do.
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And as I hope you know what I care about, is that you get that whole
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intellectual unity of this.
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Science is about that kind of intellectual unification.
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This is one of the great intellectual unifications.
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This is of the greatest stories ever told.
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And that's what the course is about.
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