Original subtitles

ERIC S. LANDER: What are we going to do in this course if we're not going

to study the whole diversity of life, and we're not going to study all of

evolution, and we're not going to study all the details of cell biology?

What we're going to do in this course is, we are going to study the

fundamental principles, and we are going to study the intellectual

unification of biology.

Fundamental principles and the intellectual unification of biology--

all of it is essentially the story of about the last 100 years.

It's about the last 100 years.

And it can be summarized in a diagram that I'm going to use again, and

again, and again.

And it's the coat of arms of this course.

And you will see the diagram essentially every lecture, and it's

going to be a you are here kind of diagram.

At any given point of the course, you're going to know where we are.

And by the time we're done, you'll truly understand the

meaning of this diagram.

We want to understand biological function--

how biology does things, how the butterfly flies this beautiful morphal

butterfly flapping its wings, flying.

How does it do it?

How does it make those wings fly?

How do the muscles work, the nerves work?

How does any of that happen?

And then the butterfly reproduces and produces more butterflies.

How does that happen?

We want to understand biological function.

Well, for a very long time, the ancient Greeks used to study

biological function by sitting around thinking hard about it.

It was a long tradition, a philosophical tradition of sitting

around thinking about things.

Aristotle, I believe, was convinced that sex determination--

whether the baby was going to be a boy or girl--

had to do with whether or not the couple conceived the child in a north

wind or a south wind.

There was no experimental data to support this.

There was a long period of time that people noticed that brains are hot,

heads are hot.

And they radiated a lot of heat.

And it was held that the brain was a radiator, a device

for dissipating heat.

It may be in many cases, but we'd like to think that it has other, more

important functions.

These are observational things without testing.

Now, don't get me wrong, observation is incredibly important.

The invention of the microscope and the ability to see cells, see

structures within cells, taught us tremendous amounts.

So I'm not dissing the power of observational biology.

But until we had analytical biology, the ability to test ideas by

experiment, we really couldn't know that we were right.

And we could be as wrong as easily as we were right about things.

The 20th century largely opens with two ways to study biology, two ways to

study biology.

One of them is called biochemistry.

Biochemistry is the idea that we can understand life by grinding it up,

fractionating it into little pieces, and studying individual components.

Biochemistry is the study of individual components purified away

from the rest of life--

one component away from the rest.

And it involves purifying that component away from

the rest, very often.

So how would a biochemist study the morphal butterfly flapping its wings

and trying to understand that?

The biochemist would start by taking the butterfly, putting it into the

blender, and homogenizing it in some way.

By the way, I'm a geneticist not a biochemist, so I get

to say these things.

The biochemist would grind it up and look for proteins or components that

might be able to slide by each other and act like muscles.

And the biochemist would be happy when she was able to take some components

out of pureed butterfly and show that they could in fact slide back and

forth without the whole rest of the butterfly.

That's biochemistry.

It's pretty powerful, though, because if you can actually make something

work without the whole rest of the butterfly, it's impressive.

You really know that you've got the cause of it.

And very often the most interesting things that the biochemists would

isolate were molecules called proteins.

Now, an utterly complimentary point of view also started essentially at the

exact same moment at the beginning of the 20th century.

And that was genetics.

Geneticists do exactly the opposite.

If biochemists study one component away from the rest of the organism,

what a geneticist does, is a geneticist studies an organism minus

one component--

the whole organism takeaway one component.

Now, how do I take away one component?

It's a mutant, a mutant organism, an organism with exactly one defect.

Something's wrong that's broken exactly one component, but you

otherwise have the whole organism there and functioning.

So here what we have is the organism minus one component,

that is to say mutants.

And geneticists didn't know what was missing.

Geneticists had no idea what was missing.

And when you don't know, you give it a name, because it

makes you feel better.

And what they called the thing that was missing, the thing that gave rise

to this trait, this thing, they called it a gene.

Gene, like generating, like genesis, beginning, making--

a gene.

For 50 years, the first half of the 20th century, biochemists did

biochemistry.

Geneticists did genetics.

Two complimentary ways of studying life.

They actually had almost nothing to say to each other.

They had nothing to say to each other, because you see, the geneticists were

studying this organism minus something, but they couldn't put their

hands on the something.

They couldn't purify the something.

They couldn't know what the thing was, but they could study the rules of

inheritance of it.

They could study the diverse things that could happen

when you made mutants.

The biochemist, they can grind up things and purify it, but they were

studying these single components in the test tube away from the rest of

the organism.

And they couldn't really tell you how it worked together

with the whole organism.

Yeah, these two things could slide by, and maybe that was

the basis of muscles.

But how would you know?

The geneticist would look for a butterfly that couldn't fly, maybe

look for 20 different kinds of butterflies that couldn't fly, start

crossing them together and asking, how many different ways can a butterfly

have a mutation that prevents it from flying?

Well, some mutations might cause no wings, some no muscles.

Some have muscles, but the muscles don't work.

But the two sides couldn't talk to each other.

And yet we knew somehow these things were connected.

The first great intellectual unification occurred at the middle of

the 20th century.

And it was the recognition that there was an intimate link

between genes and proteins.

And that intimate link between genes and proteins is what we call molecular

biology, the study of molecular biology.

And it is the genes, which it's no surprise to you.

I'm not going to be able to keep suspense up on this.

Genes are DNA.

They encode the instructions for the proteins.

But just because you learned that in kindergarten and everybody knows that

the DNA encodes proteins and things like that, you shouldn't find that to

be any less amazing.

And you shouldn't lose track of what a stunning intellectual unification

there was when genetics and biochemistry turned out to be flip

sides of the same thing.

The thing that was missing encoded those single components that were

being studied.

And the DNA was read out into RNA, an intermediate molecule which then was

used to produce proteins.

And that intellectual unification precedes Crick and Watson.

But Crick and Watson with the double helix provided such an amazing

understanding of how it is that DNA might encode those proteins.

And the next decade or two are figuring out how the DNA

encodes those proteins.

That got us to about 3/4 of the way through the 20th century.

And folks were so pleased with themselves.

They said, ahh, we have it.

We know the secret of life.

Let's stop and do something else.

But as always happens, young people come along.

And the young people said, you know, you old guys, you're so pleased you

discovered the secret of life--

genes encode proteins.

You can't actually read a single gene.

It's all theoretical.

You've proven it.

There's no doubt that that's the case--

DNA encodes the RNA and encodes the proteins.

But you haven't read a single gene.

Isn't that pathetic?

And the older generation said, well, you know, we've got the basic

principle down.

And it's not possible to purify single genes from other genes, because

they're all made out of DNA, and they all look the same.

Well, in the 1970s came an amazing revolution where it became possible to

purify single genes away from each other and to work with single genes

and read single genes, reproduce those genes and sequence those genes and

change those genes, at least in a test tube.

And that's what's called recombinant DNA.

Recombinant DNA took what was an utterly theoretical picture, a

beautiful theoretical understanding, and it made it operational.

It made it practical.

It made it possible to then say, oh, I can actually read a gene and figure

out what protein it's encoding.

Oh, I can take a protein and figure out what gene encodes it.

Oh, I might be able to knock out a gene and see

what function it subserves.

I can actually move around this diagram, and this diagram now becomes

a diagram that I can traverse around and around and around.

And that got us to the mid 1980s.

In the mid 1980s, people were so pleased with themselves.

They said, hey, we can now do this.

We can operationally read out genes and all that.

And of course, the young people came along and said, that's great.

You're all pleased with yourselves.

But you know what?

There are all these human diseases--

cystic fibrosis, and Huntington's disease, and this, and that, and the

other thing.

Can you find the genes for any of that?

Well, no, not really.

If we knew what the protein was, we could find the gene.

And if we knew what the gene was, we could find the protein.

But as it happens, we don't know either and not much we

can do about that.

And the problem was that people were studying genes one at a time.

All of the genes--

we call it the genome--

was very big, so big, that to people in the mid 1980s, it might as well

have been infinite.

And people said, we're never going to really get to it.

Or some time in the next century, we might get the whole thing.

We've got to study single components, single genes.

But an idea began getting going in the mid 1980s, which is about when I got

involved in biology, that said, why not?

Why can't we look at the whole thing?

Why can't we take a systematic look at the entire genome, all the genes

simultaneously?

And it wasn't just a question of big scale.

It's that when you look at the entirety of a picture, you see

different things.

And so it was born, standing outside--

I'll draw here this eye looking down--

genomics, global views, systematic views, of all of the

genes, all of the proteins.

And you just think about it.

If I want to study the Earth, I can go walking around on the ground and I can

see Manhattan.

I might go walking around and stumble onto the Grand Canyon or the

Mississippi.

But how do I put those pieces together unless I can get the entire Earth?

You know, it's like in the 1300s when people might know their little local

neighborhood but had no idea what the whole Earth was like.

And it turns out pretty amazing things happen.

When you look at the entire Earth, you realize that South America and Africa

kind of fit together.

And boy, it turns out to be continental drift.

And you learn amazing things at scale you don't otherwise learn.

You learn about large formations.

You can take an unbiased look.

I can find the deepest deep and the highest high and all sorts of

properties and things like that.

And that's what we've begun to do, because in the mid 1980s,

people began a process.

The biggest aspect of it was called the Human Genome Project.

And I was very much involved together with other people in the Human Genome

Project to try to read out all the information in the human genome.

And it was certifiably nuts to try to do that in the mid 1980s.

But people put together some plans.

They were pretty sketchy plans if you ask me.

But somehow people convinced the United States Congress that it was all

going to work.

Please don't ask for details.

And the Congress being very sensible, said, we understand.

If the scientific community thinks this is really going to work and is

prepared to put its neck on the line, we'll back you for a while.

We'd like to see results along the way.

And a lot of young people poured into the field and began working on a Human

Genome Project.

And by 2000, 2001, we had a rough sequence of the whole human genome.

By 2003, we had a finished sequence of the whole human genome.

That's about 10 years ago.

For about 10 years, we've had a finished sequence of

that whole human genome.

And now we can stand back, and we can get the genes associated with

particular diseases.

And we can move around this diagram not just for individual pieces but for

the whole picture.

And we see the whole thing.

And we were so pleased with ourselves, because we just had the entire world

work together to get one human genome.

It cost about $3 billion, which over 10 or 15 years isn't that all much.

It turns out that's by $300 million a year.

It's not terrible.

In terms of The National Institutes of Health budget, it's 100

times larger than that.

It was only about 1% of the National Institutes of Health budget

that went to it.

And of course it was done not just in the United States, but it was also the

United Kingdom, and France, and Germany, and Japan, and China working

together on this whole thing.

But we were so pleased with ourselves.

But of course, what if we wanted a second human genome?

Is that another $3 billion?

We've gotten pretty good.

It was down to $300 million.

But that was still pretty expensive.

What has happened in the last decade?

It's every bit as mind blowing as all the previous decades.

What's happened in the last decade, is the cost of sequencing has fallen by

about a million fold.

Whereas it was once $3 billion, it's now $3,000, $4,000, or $5,000 to

sequence entire human genome.

There's nothing that beats that that I know of in human history.

The folks who brag about Moore's Law on computers and how the cost of

electronics of storage and processing fall, and fall, and fall

exponentially.

This is much faster than that.

It's gone much faster than Moore's law-- million fold in the course of a

decade or so.

And suddenly, it means that today it's possible not to stop at sequencing

single genomes, but thousands of genomes, 10s of thousands of genomes.

And just in the past several years I've been teaching this course, I keep

telling the class how many genomes have gotten sequenced.

And I'll tell you when we get to the relevant part of the course, but it's

going to be a very large number of how many genomes have

gotten sequenced already.

And we're learning all sorts of things.

Whereas about the time you guys were born, I'll subtract the number of

genetic diseases that people really knew about was measured in the dozens.

Today, it's measured in the--

about 5,000 genetic diseases for which we have genes associated with them.

Pretty remarkable, and it's going faster and faster and faster.

So what I want you to take away more than anything is that this is a course

about something that is changing as we're teaching it.

The reason I love teaching introductory biology is because you

need to know about this.

You need to do this idea of the secret of life, because it's going to be

affecting everything we do.

It's going to be in the newspapers.

There will be unpredictable things that are happening

every week, every month.

And you need the fundamentals to understand what that's about.

This is understandable stuff.

It's amazing stuff.

We are going to come back again, and again, and again to this diagram--

genetics, biochemistry, and molecular biology that connects them, the

recombinant DNA, the genomics, and then the amazing things that are going

on right now, the ideas that are even unimaginable.

Writing software for cells and DNA, changing what cells do.

There's all sorts of folks who are saying, oh, you guys are all so

pleased with yourself.

But there's so much more we could be doing.

And there are people here at MIT and people all over the world thinking

about what the next revolution is about.

Anyway, that's what the course is about.

It's what it's not about.

There's things we're not going to be able to do, and the things we are

going to be able to do.

And as I hope you know what I care about, is that you get that whole

intellectual unity of this.

Science is about that kind of intellectual unification.

This is one of the great intellectual unifications.

This is of the greatest stories ever told.

And that's what the course is about.