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Just wanted to begin today by
pointing out a couple of articles

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from today's Boston Globe.
There's an article that's on the

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financial pages about investors
reconsidering gene therapy,

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and startups funded as technology
evolves.  A lot of you have heard

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the words gene therapy.
A lot of you, at the end of that

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bacterial genetics lecture,
said you weren't quite sure what

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complementation was.
But, gene therapy is basically

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complementation but to work.
The idea is if you got a broken

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gene, and you can put in a good copy,
then you'll take the cell back to

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being normal, which is exactly what
we're doing in those phage crosses

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where we had two phage,
one with the mutant copy of the gene,

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and one with the wild type copy of
the gene.  And they're saying here

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that there's a renewed interest.
Now, the basic strategy in these

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things is to take usually a
retrovirus, the same kind of idea

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that we heard about with the HIV-1
virus that will make a DNA copy,

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and then the copy gets inserted
somewhere in the chromosome.

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So, the good thing is it puts and a
new copy in a chromosome.

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The bad thing is you got a piece of
DNA being stuck somewhere in the

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chromosome.  And there are places
where it can go where it doesn't

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matter, and there are other places
where it really does matter.

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So, it's been a very tricky business
with gene therapy.

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Part of the thrust here is they're
thinking that maybe they need to

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pick targets were the person's going
to die anyway so that if there is a

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risk of getting cancer or something,
it's outweighed by the possible

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thing.  That's sort of the thrust.
You can see the article; it's in

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today's paper.
It's very timely for what we are

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talking about now.
And then on Friday I'm going to

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start talking about recombinant DNA
strategies and stuff.

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But there's another article in
today's paper.

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This is one of those things that I
told you about where an article is

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published in the,
in this case, online in the journal

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nature.  They have an embargo on a
press thing until Thursday or so,

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and then the article is on, the hot
papers that have just come out show

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up in the newspapers,
usually either on Friday or Monday.

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And this is yet another system that
they describe as making a molecular

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repair kit that corrects mutations
in the cells' DNA.

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So far, this has only been done in
cells.  But it's working well enough,

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and the article is saying this
approach could become a serious

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competitor to conventional gene
therapy.  In here,

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you have sort of a layman's account
of this kind of complementation by

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gene therapy.  We're talking about
gene therapy in that field which

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attempts to force feed healthy genes
into cells hobbled by defective ones

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has been plagued by failure,
and recently was found to cause

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leukemia in some patients.
That's probably because of the

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insertion events associated with
these viruses.

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This new system rewrites the small
stretch of misspelled genetic code.

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That's typically the reason the
gene has gone bad.

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So it's a different kind of
strategy.  This is the first report

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I've heard of that.
Some of the stuff we're talking

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about is sort of inescapable because
you're going to see

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it in the paper.
Here, they're telling you the sort

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of thing I was just saying.
The viruses inject their payloads

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at random within the cells tangled
mass of DNA sometimes disrupting

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normal genes.  Even when genes land
in good locations,

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the molecular machinery that
regulates their activity is also

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often thrown off,
leaving the healthy genes operating

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at a level to low to be helpful or
functioning in the wrong parts of

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the body.  It must begin to sound
familiar.  You stick a random piece

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of DNA somewhere,
you can disrupt the regulation in

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the gene as well as just landing in
the open reading frame.

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So there's a problem with gene
therapy.  Now,

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they'd like to make you think that
this is going to be the promised to

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everything, but as always it's more
complicated.  And so,

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I just picked up the last paragraph
of this article.

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Other scientists said the approach
looked promising,

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but predicted it would end up
struggling with this problem of its

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own, James M. Wilson,
a gene therapy researcher at the

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University of Pennsylvania.
Now, there's somebody who's in a

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position to criticize,
but also has a vested interest

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himself and the alternative therapy,
noted that the first step of the new

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process causes for [zinc
fingers?].

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It's a kind of protein that's
involved in this,

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to make a fresh break in DNA to
accommodate the insertion of the

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corrected sequence.
It's the same kind of break it with

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radiation that can lead to cancer.
And we're going to talk today about,

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you'll see where double-stranded
breaks and whatnot can be a real

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problem in terms of the integrity of
the DNA and genome stability,

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which is maintaining gene stability
so important in avoiding cancer.

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You guys are a tough crowd.
Comments ranged from, this was the

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best lecture that I'd given to ones
that were absolutely the other end

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of the spectrum.
You're a very hard group.

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I truly am going to take, I don't
have time really to sit back and

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redo all my lectures,
but I've a huge amount of input,

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and I'm going to go back over all
this input and getting,

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and take it very seriously in terms
of how I go about things next year.

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I can see a number of changes and
going to make.

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Whoever sent me the e-mail that
talked about the Dock Street

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Bohemian Pilsner brewed in Utica,
NY, this classic golden Pilsner,

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pungent, perfumy taste and so on,
it was a moment of lightness, but if

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I got to many things like that it's
not going to hell in a contract to

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figure out how to do.
For the person who asked about how

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to avoid accidental pollination,
when they're going to do that, they

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actually take the stamens off the
flowers so you don't get accidental

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self fertilization.
You actually go out and make ones

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that are just male or just female
flowers.  You can do that rather

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easily.  OK, so what we got into
last time, or what I told you last

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time, and I promise you that there's
another Mendel lecture coming.

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For those of you who thought this
was a little slow,

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you may find the next one is all too
fast.  But anyway,

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that will be how it goes.
Mendel had carried out this

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fundamental series of experiments.
And I did linger over it because I

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think it's so simple you can
actually see the scientific process

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in action, and it also isn't
complicated by any techniques that

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we can't see.  And it was a
tremendously important insight that

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genetic information came in units.
But as I told you,

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it wasn't accepted because for most
of the world at the time,

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it was a statistical argument.
There weren't any entities that

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were two of inside a cell,
and all that sort of thing.

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So, it didn't take over scientific
thinking.  It wasn't until about

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1900 when several other geneticists
did finally find the systems that

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duplicated Mendel's results,
and therefore showed that these were

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general inferences,
something that Mendel himself,

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as I told you, by choosing weeds and
bees as follow-up systems

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hadn't been able to do.
These other geneticists showed them

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in other systems.
But the other thing that made the

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difference at the time,
was by this point cytologists,

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who were looking at cells under
microscopes, had found entities

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whose behavior seemed to match those
of these particles of information

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that Mendel had postulated to
explain these patterns of

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inheritance that he was seeing.
These particles,

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because they were called chromosomes,
which literally means colored things,

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the reason they were colored was not
because they were inherently colored,

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but because cytologists were
staining the cells with a variety of

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things.  And that was what allowed
them to visualize these.

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And so, by staring into microscopes,
right around this time, around the

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turn of the century,
1900s or so, cytologists had come up

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with three key observations.
One was that chromosomes came in

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matched pairs.
So, let's say in this cell,

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there were too long and too short.
So that's a chromosome.  And a

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correspondence,
we now know, to double-stranded DNA

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molecule that's been
all condensed up.

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And there are two copies of each
chromosome in this thing.

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So: too long, too short, one came
from mom, one came from dad.

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And for bookkeeping purposes,
I'm going to color them so that from

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one parent is unshaded,
and the other one is shaded.

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Most of you know in human cells we
have 23 pairs of chromosomes.

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This is a now fancier method of
visualizing chromosomes called

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[peating?] chromosomes where you
take little stretches of DNA that

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are unique to particular sequences,
attached dyes, and then use them to

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[stain?] the cells,
and so they will color only

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particular chromosomes.
And we have 22 pairs of identical

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chromosomes, and then the sex
chromosomes here,

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X and Y, this would be a male,
or two Y's if we were female.

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We'll return to those in the next
lecture.  Kim Naismith,

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who spent his life working on how
these chromosomes segregate gave a

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talk a year ago.
He's in London at a hospital in

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London.   And then he brought in the
next slide.  There was an artist who

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spent several months visiting with
him, trying to find ways to

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represent in art some of what she
saw going on.  And I thought you

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might enjoy seeing this,
the slide.  This is the human

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complement of chromosomes,
represented in stripy socks that

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various staff members from the
hospital brought in for

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her to do this.
So, a little touch of scientist

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humor which some of you may think is
pretty nerdy, but anyway there it

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was for what it's worth.
He showed that in our departmental

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[colloquium?].
OK, the second thing,

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then, that the cytologists noted by
staring at this was during ordinary

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cell division,
which gives two identical daughters

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the numbers of chromosomes
per cell is preserved.

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And this ordinary cell division is

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given a special name of mitosis.
So if we take this cell, the first

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thing that happens,
then, is the chromosomes are

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duplicated.
We've talked a lot about DNA

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synthesis at the molecular level.
This is looking at it.  Excuse me,

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and so, there are now two DNA
molecules, that each one of these

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new DNA molecules is given
a special name.

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This is called a chromatid.
So there was one DNA molecule here.

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It's now duplicated, but you'll
notice these are still joined

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together.  The point at which they
are joined together is known as the

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centrosome.  And then,
after this, after the DNA's been

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copied, these things are lined up at
the center of the cell and then they

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are pulled apart to give two
daughter cells that are just like

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what you started with.
This part, so this is 2N,

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if N is the number of kinds of
chromosomes.  And then there's two

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each.  This is 2N.
At this point, the DNA contents of

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the cell is 4N.
This is 2N.  This is 2N.

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We're back to where we started.
This part was invisible to the

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cytologists, at least in the sense
the chromosomes at this point are

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extended.  And so,
they weren't able to visualize them

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by looking through the microscope.
But as it came time for cell

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division, then the chromosomes
condensed up very tightly.

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This is probably to avoid tangles.
And you need to pull them apart

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into the two daughter cells.
And then the part that could see

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them, this was known as mitosis,
this process by which the

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chromosomes are pulled apart.
So, mitosis is a mechanism for

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nuclear division that results in two
daughters with identical

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genetic information.

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When you contrast this to meiosis,
which I'll show you in just a minute,

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this has been studied for years in a
kind of observation way.

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I showed you at some point.
This is an animal cell where the

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chromosomes line up,
and then they pull apart.

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I think I showed you, and you can
see the cells divide once they've

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done that.  I'm going to show you
this next thing,

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which everything happens more slow
motion.  This is a picture of the

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blood lily, so it's a plant.
Again, the choice of model system

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is often, if it has a feature that
is good for a particular thing.

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This happens, very easy to visualize
in these lily cells.

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Now here, the cells have duplicated
their chromosomes,

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and the daughter chromosomes are
held together.

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They're glued together,
so you can tell in this thing that

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they've been glued.
Now, in order to separate the first

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thing they have to do is line up at
the equator of the cell.

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And then it pulls apart and you can
see that each daughter cell gets one

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of the duplicated chromosomes.
OK, so that's mitosis.

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It generates two copies of what you
started with.  The other observation

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that the cytologists made was that
cell divisions that produce sex

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cells work by a different system.
So, the third thing,

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And, I'm going to give you the

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scientific word now for sex cells.
So, they're usually called gametes.

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General term, so that would be
sperm and egg,

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or pollen would be a kind of gamete.

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In this process,
the number of chromosomes is halved.

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And this special type of cell
division is known as meiosis.

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It's very important, because if we
didn't have meiosis we wouldn't

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have any progeny.
We need to be able to cut the number

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of chromosomes we have per cell in
half, so as Mendel inferred,

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then when each parent made a
contribution you'd be back up to the

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right number of cells.
Now, so this process begins again

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by duplication of the DNA.
So this would be 2N.

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Now we go to, as before,
with one interesting difference here.

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So we are at 4N in the cell.

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But you notice that drawing these
duplicated chromosomes with

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chromatids overlapping.
This point of, I didn't do this too

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well.  The point of connection: what
are the two chromosomes overlap is

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known as the chiasma.
It's a point of actual physical

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interaction between
the chromosomes.

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And what it allows the cell to do is
to have the two homologous

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chromosomes, in this case the two
long ones, find each other,

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and actually physically interact.
That's a critical event for the

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next step that I'm going to show you.
It's also a point,

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which you'll see in the next lecture.
There is additional genetic

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diversity introduced
into the system.

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So, at this point,
what's happened is that the DNA has

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doubled, at this point,
looks sort of like mitosis except

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for the fact that the duplicated
chromatids have overlapped.

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There's a least one of these for
every pair of duplicated chromosomes.

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So what happens in the next phase,
which is known as meiosis I is that

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the pairs of duplicated chromosomes
are separated.

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So, we get two cells.
We might get, say, the unshaded of

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this one and the shaded of the
little guys.  And the other one then

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is shaded with a long one,
and shaded with this one.  This is

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2N, and this is 2N.
But if you'll take a look at what's

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happening over here,
you will see that we don't have the

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same thing going on.
In that case, we were producing

245
00:21:06 --> 00:21:11
identical copies of the starting
cell.  In this case,

246
00:21:11 --> 00:21:16
we've got something different now
because we've separated both copies

247
00:21:16 --> 00:21:21
of, let's say,
the chromosome from dad from both

248
00:21:21 --> 00:21:26
copies of the chromosome that
originated with mom,

249
00:21:26 --> 00:21:31
and the other way over here.
These, then, undergo a second round

250
00:21:31 --> 00:21:37
that's known as meiosis 2,
which resembles now mitosis in the

251
00:21:37 --> 00:21:44
sense that the duplicated chromatids
are now pulled apart into daughter

252
00:21:44 --> 00:21:51
cells so that this one will generate
what long, unshaded one,

253
00:21:51 --> 00:21:58
one short, and there will be two of
those.  In the cell,

254
00:21:58 --> 00:22:06
it will generate a shaded long and
unshaded like that.

255
00:22:06 --> 00:22:11
So now, there are four of these.
And you'll notice that there is now

256
00:22:11 --> 00:22:17
an N.  So, we have the number of
chromosomes during meiosis via a

257
00:22:17 --> 00:22:23
process by two rounds of division.
The other thing you can think of is

258
00:22:23 --> 00:22:28
you can begin to see,
at least, when the evolution of sex

259
00:22:28 --> 00:22:34
was such a powerful force in driving
evolution by introducing so much

260
00:22:34 --> 00:22:40
variation, because each of us has a
copy of each of our 22 chromosomes

261
00:22:40 --> 00:22:46
where we have homologous pairs,
one from mom, one from dad.

262
00:22:46 --> 00:22:50
That every time we make a sex cell,
a sperm or an egg, what happens is

263
00:22:50 --> 00:22:55
for chromosome 1,
you can either get a copy from mom

264
00:22:55 --> 00:23:00
or the copy from dad.
And then the next one: copy from

265
00:23:00 --> 00:23:05
mom, copy from dad, and so on.
You can see the variation is

266
00:23:05 --> 00:23:11
possible just from that part of the
process alone.

267
00:23:11 --> 00:23:16
And there's going to be more
variation that come about from

268
00:23:16 --> 00:23:22
events that happen where this
chiasma is as I'll show you.

269
00:23:22 --> 00:23:27
So, meiosis then, as I said,
is a mechanism for nuclear division

270
00:23:27 --> 00:23:33
that produces four daughter cells
with half the genetic info

271
00:23:33 --> 00:23:39
of the original.
So, how did I write that?

272
00:23:39 --> 00:24:19
And in this case,

273
00:24:19 --> 00:24:31
the daughters are not identical.
Does somebody have a question?

274
00:24:31 --> 00:24:39
Yeah?
Oh, this part of the process,

275
00:24:39 --> 00:24:44
the cytologists broke this down when
they were observing.

276
00:24:44 --> 00:24:49
So, it was a part they couldn't see.
When they started to be able to see

277
00:24:49 --> 00:24:53
it, they first saw this one division,
and then the second division.

278
00:24:53 --> 00:24:58
They called the first round or
division of meiosis 1, and

279
00:24:58 --> 00:25:06
the second meiosis 2.
So it was just a name given to the

280
00:25:06 --> 00:25:16
process.  Yeah?
Oh, sorry, excuse me,

281
00:25:16 --> 00:25:26
I see the problem.  OK,
it goes this way.  This period of

282
00:25:26 --> 00:25:36
time is called meiosis 1.
That part of the process is called

283
00:25:36 --> 00:25:43
meiosis 1, meiosis 2, sorry.
Yeah, I mean what I wrote down as

284
00:25:43 --> 00:25:49
arbitrary.  You could've had to for
mom, and two from dad.

285
00:25:49 --> 00:25:54
And in fact, I guess if we have 22
pairs we could eventually have a

286
00:25:54 --> 00:26:00
sperm or egg that had all of the
copies from mom, and all

287
00:26:00 --> 00:26:05
of the copies from dad.
You could calculate the statistical

288
00:26:05 --> 00:26:09
chances of that happening,
but what you'll discover as we'll

289
00:26:09 --> 00:26:14
find next time,
is that even if you did that the

290
00:26:14 --> 00:26:18
chromosomes would no longer be
identical to what you got from mom

291
00:26:18 --> 00:26:23
or dad, because there's a little bit
of genetic recombination going on

292
00:26:23 --> 00:26:27
during that process.
I'll also show in a minute that you

293
00:26:27 --> 00:26:32
can get errors in this process,
and that these are important.

294
00:26:32 --> 00:26:37
So, what happens then is that
fertilization,

295
00:26:37 --> 00:26:42
what the cytologists can see
happened was that the number of

296
00:26:42 --> 00:26:47
chromosomes have been halved.
So, you had N plus N giving you 2N

297
00:26:47 --> 00:26:52
where this might be,
for example, the egg,

298
00:26:52 --> 00:26:57
and this might be the sperm,
since gametes have half the number

299
00:26:57 --> 00:27:02
of genetic content when they fuse,
then you go back to the original

300
00:27:02 --> 00:27:08
number.
And this gave rise to what was known

301
00:27:08 --> 00:27:16
as the chromosomal theory of
inheritance.  Even though

302
00:27:16 --> 00:27:24
cytologists didn't know what these
colored things were,

303
00:27:24 --> 00:27:32
they seemed to have the properties
that you would expect the carriers

304
00:27:32 --> 00:27:38
of the genetic information to have.
Be duplicated before a cell was

305
00:27:38 --> 00:27:42
going to divide and then they seemed
to be very precisely segregated so

306
00:27:42 --> 00:27:46
that each daughter cell got one copy.
And it made sense,

307
00:27:46 --> 00:27:51
then, in terms of the formation of
sex cells you'd have,

308
00:27:51 --> 00:27:55
and then it would all come back up.
So, the cytologists proposed this

309
00:27:55 --> 00:27:59
chromosomal theory of inheritance.
Chromosomes were the carriers that

310
00:27:59 --> 00:28:04
carried the genetic information.
And you can see now that Mendel's

311
00:28:04 --> 00:28:08
work was rediscovered,
which is more or less what happens

312
00:28:08 --> 00:28:13
around 1900, how beautifully it
mapped on top of this because the

313
00:28:13 --> 00:28:17
genetic information came in
particles.  You'd think,

314
00:28:17 --> 00:28:22
oh, well those particles are sitting
on those chromosomes.

315
00:28:22 --> 00:28:26
They get duplicated.  They get
separated.  They get divided in half.

316
00:28:26 --> 00:28:31
Their number gets divided in half
when you make sex cells.

317
00:28:31 --> 00:28:36
So, I want to at least point out,
let me go onto this next thing here.

318
00:28:36 --> 00:28:41
Here was one other picture I'd
shown you.  This was a cancer cell

319
00:28:41 --> 00:28:46
dividing again.
We see the same process at work.

320
00:28:46 --> 00:28:52
And that just reminds you, when I
was talking about that kind of

321
00:28:52 --> 00:28:57
process, trying to remind you that
one cell gives rise to two cells,

322
00:28:57 --> 00:29:03
and one DNA molecule gives rise to
two DNA molecules.

323
00:29:03 --> 00:29:06
But these phenomena are related
[even no one tends?

324
00:29:06 --> 00:29:10
to talk about in different parts of
the courses, and if you've got more

325
00:29:10 --> 00:29:14
than one DNA molecule per cell,
then each one's a chromosome.  And

326
00:29:14 --> 00:29:18
then you have to take care of
segregating those as well.

327
00:29:18 --> 00:29:22
But a point that I'd made is that
up until this part at the right

328
00:29:22 --> 00:29:26
could be a yeast or an E.
coli, but if it's going to be

329
00:29:26 --> 00:29:30
someone, something more complicated
that's got different kinds of cells

330
00:29:30 --> 00:29:34
like us, then we have these
ultimately, an adult human

331
00:29:34 --> 00:29:39
with 1014 cell.
So, this process has happened over,

332
00:29:39 --> 00:29:45
and over, and over again.  And it
has to be really very accurate.

333
00:29:45 --> 00:29:52
And, there was remarkable advances
have been made in understanding this

334
00:29:52 --> 00:29:59
process over the last few years.
And a lot of this was due to the

335
00:29:59 --> 00:30:06
work of Lee Hartwell,
who carried out experiments,

336
00:30:06 --> 00:30:11
I guess, that offered some key
insights into the basis of the whole

337
00:30:11 --> 00:30:16
cell cycle, of which this is just
part.  So they said,

338
00:30:16 --> 00:30:21
here we can't really see all of this
stuff in the microscope.

339
00:30:21 --> 00:30:26
What cytologists were able to
observe was that after the

340
00:30:26 --> 00:30:31
chromosomes had duplicated,
then they condensed up.  They became

341
00:30:31 --> 00:30:36
visible, and they could see that
part of the system.

342
00:30:36 --> 00:30:41
So, a great body of knowledge has
been learned over the past few years.

343
00:30:41 --> 00:30:46
Lee Hartwell,
who was a postdoc at MIT with Boris

344
00:30:46 --> 00:30:51
Magasanik a number of years ago,
was one of the key people who led to

345
00:30:51 --> 00:30:56
this round of insights.
And what we now know, the cell

346
00:30:56 --> 00:31:02
cycle can be basically divided
into four parts.

347
00:31:02 --> 00:31:07
So a newly born cell,
if you will, undergoes what's known

348
00:31:07 --> 00:31:12
as phase of the cell cycle that's
known as the G1 phase.

349
00:31:12 --> 00:31:18
And you could think of this as,
amongst other things, sort of

350
00:31:18 --> 00:31:23
preparation for duplicating the
cell's DNA.  And then,

351
00:31:23 --> 00:31:29
there's a phase known as the S-phase,
which is what DNA synthesis

352
00:31:29 --> 00:31:35
takes place.
That now gives the cell and

353
00:31:35 --> 00:31:42
information content of 4N.
There was then another phase known

354
00:31:42 --> 00:31:48
as G2, which you could think of as
preparation for pulling the

355
00:31:48 --> 00:31:55
chromosomes apart,
and for the cell dividing.

356
00:31:55 --> 00:32:01
And that's known as mitosis.
And so, this is quite remarkable.

357
00:32:01 --> 00:32:07
It's quite fundamental.  It's a
very elegant and very complex system

358
00:32:07 --> 00:32:12
of controls.  And what Lee learned
is that there is an elaborate system

359
00:32:12 --> 00:32:18
of what we now know as checkpoints
in the cell cycle.

360
00:32:18 --> 00:32:23
And the idea is pretty much the
same sort of thing that you might do

361
00:32:23 --> 00:32:29
if you were an engineer and you were
setting up a quality control process

362
00:32:29 --> 00:32:34
that involved a series of stages.
And what a checkpoint does is it

363
00:32:34 --> 00:32:38
basically commands successful
completion of a prior phase before

364
00:32:38 --> 00:32:42
the system is permitted to move to
the next stage.

365
00:32:42 --> 00:32:46
And you can sort of see the problem
here, that if you are trying to,

366
00:32:46 --> 00:32:50
say you're copying your chromosome,
your DNA, and you only got part way

367
00:32:50 --> 00:32:54
through.   And then he proceeded to
the part where you pulled the

368
00:32:54 --> 00:32:58
chromosomes apart.
There would be all kinds of chaos

369
00:32:58 --> 00:33:02
inside of the cells because you
would be breaking chromosomes.

370
00:33:02 --> 00:33:09
You wouldn't be getting identical
information.  And there are three

371
00:33:09 --> 00:33:17
major checkpoints.
There is a checkpoint at the G1 S

372
00:33:17 --> 00:33:25
boundary.  There is actually more
than one.  But there's an intra-S

373
00:33:25 --> 00:33:33
phase checkpoint,
and then there's another one at the

374
00:33:33 --> 00:33:39
G2 M boundary as well.
And the way that Lee found this out,

375
00:33:39 --> 00:33:43
I wanted to just take you back
because remember when I was talking,

376
00:33:43 --> 00:33:47
well, first we talked about how
would you get an mutant affecting an

377
00:33:47 --> 00:33:52
essential cell,
a gene whose function is essential

378
00:33:52 --> 00:33:56
for the cell.  [He said?
you'd have to be conditional in

379
00:33:56 --> 00:34:00
some kind of  way,
because the organism would be dead,

380
00:34:00 --> 00:34:05
and couldn't use genetics to study
it.  So, when I introduced you to

381
00:34:05 --> 00:34:09
those phage, and we wanted to study
critical functions needed for phage

382
00:34:09 --> 00:34:13
growth, we needed a conditional
mutant.  Remember,

383
00:34:13 --> 00:34:18
we did look for temperature
sensitive mutants.

384
00:34:18 --> 00:34:22
So that's what Lee Hartwell started
to do with yeast in 1970

385
00:34:22 --> 00:34:27
approximately.
He just looked for mutations that

386
00:34:27 --> 00:34:32
were temperature sensitive
lethals in yeast.

387
00:34:32 --> 00:34:35
Now, yeast can be diploid,
but they also can be haploid,

388
00:34:35 --> 00:34:39
which is just one copy of genetic
information.  So just like the

389
00:34:39 --> 00:34:43
bacteria [haploid yeast?
, if you get a mutation affecting a

390
00:34:43 --> 00:34:46
gene, then you see its phenotype
right away because there isn't a

391
00:34:46 --> 00:34:50
complication of the second
chromosome.  And Lee got the Nobel

392
00:34:50 --> 00:34:54
Prize for his work,
just, I forget, three years ago or a

393
00:34:54 --> 00:34:58
short time ago anyway.
And so, this was the process he was

394
00:34:58 --> 00:35:01
studying.
I showed you this movie.

395
00:35:01 --> 00:35:05
In this case, this is budding yeast,
and you can see why it's called

396
00:35:05 --> 00:35:09
budding yeast is that rather than
the still growing and segregating

397
00:35:09 --> 00:35:13
down the middle,
the daughter cells grow as little

398
00:35:13 --> 00:35:16
buds coming off the side.
The DNA is still going to be

399
00:35:16 --> 00:35:20
duplicated as we got,
and then segregated into the

400
00:35:20 --> 00:35:24
daughter.  So that part of the
process is there,

401
00:35:24 --> 00:35:28
but there's yeast growing sped up a
bit so you can see it.

402
00:35:28 --> 00:35:32
So, what we found was that when he
looked at his TS mutants,

403
00:35:32 --> 00:35:36
he found that they tended to arrest
at characteristic stages,

404
00:35:36 --> 00:35:41
and he was able, then, to figure out
that there must be some sort of

405
00:35:41 --> 00:35:45
checkpoint system that is something
went wrong during one of the faces,

406
00:35:45 --> 00:35:50
then the cells with all pile up at a
particular characteristic stage in

407
00:35:50 --> 00:35:54
the cell cycle.
And this was controlled by these

408
00:35:54 --> 00:35:59
checkpoints.
These checkpoints are of enormous

409
00:35:59 --> 00:36:04
importance because if something goes
wrong with them,

410
00:36:04 --> 00:36:08
as happens often in cancer cells,
then you get a huge increase in

411
00:36:08 --> 00:36:13
instability of the genome very
similar to the way,

412
00:36:13 --> 00:36:18
using, for example, mismatch repair
causes instability of the genome and

413
00:36:18 --> 00:36:22
therefore things that can cause a
cell to forget to divide when it

414
00:36:22 --> 00:36:27
stopped dividing when it hits its
neighbors, which part of the cell it

415
00:36:27 --> 00:36:32
belongs to and so on.
Those kinds of changes will come

416
00:36:32 --> 00:36:36
with much greater frequency.
Another thing that was completely

417
00:36:36 --> 00:36:41
remarkable was because it was yeast
it was relatively easy to find genes

418
00:36:41 --> 00:36:46
that were broken.
Going back to complementation,

419
00:36:46 --> 00:36:50
leaving aside the technicalities,
if we had a mutant that's a TS

420
00:36:50 --> 00:36:55
lethal and it's dead,
if we put a good copy we'll know it

421
00:36:55 --> 00:37:00
because the cell won't die at a high
temperature anymore.

422
00:37:00 --> 00:37:03
So, you can sort of see from the
first principle it was relatively

423
00:37:03 --> 00:37:06
straightforward to find the genes in
yeast that are necessary for cell

424
00:37:06 --> 00:37:10
cycle control.
The remarkable thing is that

425
00:37:10 --> 00:37:13
they've been concerns all the way up
to humans that the proteins that are

426
00:37:13 --> 00:37:17
involved in the cell cycle control
are virtually identical in humans.

427
00:37:17 --> 00:37:20
So, the system, again, is probably
locked into place because it works

428
00:37:20 --> 00:37:24
so well.  And once it was working,
then evolution didn't have a lot of

429
00:37:24 --> 00:37:27
space.  I won't say it's completely
identical in human cells,

430
00:37:27 --> 00:37:31
for example, have a few more
wrinkles that they throw away.

431
00:37:31 --> 00:37:36
And fundamentally,
you can see evolutionarily that the

432
00:37:36 --> 00:37:41
system [involved once?
.  One thing I just want to comment

433
00:37:41 --> 00:37:46
on, and here's just an example of
the sort of thing that can happen if

434
00:37:46 --> 00:37:51
you get a problem with pulling
chromosomes apart when they're not

435
00:37:51 --> 00:37:56
ready, or something happens that
make a break in a chromosome.

436
00:37:56 --> 00:38:01
You will get a double strand break,
and cells don't like that, and they

437
00:38:01 --> 00:38:06
try and fix it up.
I think in this case,

438
00:38:06 --> 00:38:10
you can see the chromosome 9 has
picked up a piece of a couple of

439
00:38:10 --> 00:38:14
other chromosomes.
This piece here came from

440
00:38:14 --> 00:38:18
chromosome 8 over here,
and this piece here came from

441
00:38:18 --> 00:38:22
chromosome 22.
And so, this cell now has things

442
00:38:22 --> 00:38:26
kind of messed up.
And this particular chromosome's

443
00:38:26 --> 00:38:30
got parts of two other chromosomes.
And so, you can start to think

444
00:38:30 --> 00:38:35
about the consequences of that.
You'll see when you start

445
00:38:35 --> 00:38:39
segregating chromosomes,
there are issues.  And also,

446
00:38:39 --> 00:38:43
the junctions themselves can
sometimes do things like creating

447
00:38:43 --> 00:38:48
fusion proteins that have aberrant
properties, for example,

448
00:38:48 --> 00:38:52
a signaling molecule that's now
locked permanently into the on

449
00:38:52 --> 00:38:57
position or something like that.
Those sorts of things can happen by

450
00:38:57 --> 00:39:01
these as well.
So, here's a very abbreviated form,

451
00:39:01 --> 00:39:05
the principal that happens, or what
happens so that the chromosomes

452
00:39:05 --> 00:39:10
become visible in the microscope.
There is about a couple of meters of

453
00:39:10 --> 00:39:14
DNA in every human cell.
So, you can see almost from first

454
00:39:14 --> 00:39:18
principles, it almost has to be
packaged in some way to fit in that

455
00:39:18 --> 00:39:22
little, tiny area.
And down at the basic level,

456
00:39:22 --> 00:39:26
the DNA is looped around a little
cluster of proteins called histones.

457
00:39:26 --> 00:39:30
And then, as the cells approach the
mitotic stage,

458
00:39:30 --> 00:39:34
they package these and higher,
and higher, and higher levels of

459
00:39:34 --> 00:39:38
packaging so that the chromosomes
get more and more compact,

460
00:39:38 --> 00:39:42
and therefore less like spaghetti,
and less likely to get tangled when

461
00:39:42 --> 00:39:46
they are pulled apart.
Now, this teaching as part of the

462
00:39:46 --> 00:39:50
course.  It's in the book.
It's a little like glycolysis,

463
00:39:50 --> 00:39:54
though, and there's so much detail.
It's hard to notice at all.  And

464
00:39:54 --> 00:39:58
what I've tried to do here is just
sort of take a step back,

465
00:39:58 --> 00:40:02
focus you on the really big parts of
the process.

466
00:40:02 --> 00:40:06
But you can see this is a sort of
typical textbook thing showing you

467
00:40:06 --> 00:40:10
the various sub stages of this
process that cytologists have given

468
00:40:10 --> 00:40:14
names to each part of this.
For example, you can see the

469
00:40:14 --> 00:40:19
chromosomes lining up at the
equatorial phase just before they're

470
00:40:19 --> 00:40:23
going to be pulled apart.
One little detail which I glossed

471
00:40:23 --> 00:40:27
over at this point as you can see
that the chromosomes are,

472
00:40:27 --> 00:40:32
of course, surrounded by the nuclear
membrane.

473
00:40:32 --> 00:40:35
And, at least in many cells,
what happens is just before the

474
00:40:35 --> 00:40:39
chromosomes are going to be pulled
apart, this nuclear membrane in a

475
00:40:39 --> 00:40:42
matter of 20 or 30 seconds goes from
being a membrane into sort of

476
00:40:42 --> 00:40:46
breaking into a whole little series
of membrane sacs.

477
00:40:46 --> 00:40:50
And then, after the chromosomes
have pulled apart,

478
00:40:50 --> 00:40:53
now you reassemble the nuclear
membrane around each set of

479
00:40:53 --> 00:40:57
chromosomes.  And I think there's
still an awful lot to be learned

480
00:40:57 --> 00:41:01
about how that particular trick is
done.  And that's a

481
00:41:01 --> 00:41:05
textbook diagram.
These are the kinds of things the

482
00:41:05 --> 00:41:09
cytologists were looking at as they
were describing it.

483
00:41:09 --> 00:41:14
And one thing you can certainly see,
I think, is that there are a lot of,

484
00:41:14 --> 00:41:18
if you want to think of them as
cables, this whole process is done

485
00:41:18 --> 00:41:23
by molecular machinery.
And in fact, one of the key things

486
00:41:23 --> 00:41:27
for ensuring that the chromosomes
are all lined up is each are

487
00:41:27 --> 00:41:33
attached to each poll of the cell.
So, an individual chromosome feels

488
00:41:33 --> 00:41:39
tension on both sides,
and there's pretty good evidence at

489
00:41:39 --> 00:41:45
this point that says that what has
to happen before mitosis is allowed

490
00:41:45 --> 00:41:51
to proceed is that each duplicated
chromosome must feel the tension on

491
00:41:51 --> 00:41:57
both sides.  And if one of them is
only attached on one side,

492
00:41:57 --> 00:42:02
it's not allowed to go ahead.
Here are a couple more pictures.

493
00:42:02 --> 00:42:08
The chromosomes are in blue, and
all this cabling is in green.

494
00:42:08 --> 00:42:14
You can see a molecular machine's
basically at work.

495
00:42:14 --> 00:42:19
And I wanted to show you this
picture because this is important.

496
00:42:19 --> 00:42:25
There's two parts to this.  Julie,
could you hit?  So, this is a normal

497
00:42:25 --> 00:42:31
mitosis.  These are in lung cells
from a newt, which are very flat.

498
00:42:31 --> 00:42:34
So it's easy to visualize them.
I believe this is by Nomarski, a

499
00:42:34 --> 00:42:38
kind of optics called Nomarksi
optics.  What they're doing,

500
00:42:38 --> 00:42:42
the duplicated chromosomes are
getting lined up at the equatorial

501
00:42:42 --> 00:42:46
position in the cell,
and you get a spindle attached to

502
00:42:46 --> 00:42:50
one side, and then a spindle
attached to the other.

503
00:42:50 --> 00:42:54
And once that's happened,
then you can see the chromosomes.

504
00:42:54 --> 00:42:58
Watch this one over here, for
example.  It just got attached,

505
00:42:58 --> 00:43:02
and it's being pulled into the
middle.

506
00:43:02 --> 00:43:07
And once the cells feel that all the
attention, there's tension on all of

507
00:43:07 --> 00:43:12
them, and then it enables the next
stage of the process.

508
00:43:12 --> 00:43:17
And you will see each of the
daughter chromatids segregate before.

509
00:43:17 --> 00:43:22
And, I just want to impress upon
you it's complicated enough just

510
00:43:22 --> 00:43:27
replicating the DNA at the [fidelity?
.  We talked about an awful lot of

511
00:43:27 --> 00:43:32
other stuff has to go on.
And it would be a reasonable

512
00:43:32 --> 00:43:36
question: is there ever a mistake?
And there is.  This one actually

513
00:43:36 --> 00:43:40
shows another cell where there's
going to be a mistake.

514
00:43:40 --> 00:43:44
You can't see it yet, but you can
see the chromosomes are all

515
00:43:44 --> 00:43:48
condensed up.  And they are
beginning to get these spindles

516
00:43:48 --> 00:43:52
attached.  And as they get attached
to the site then they get localized

517
00:43:52 --> 00:43:56
in the central part right down the
equatorial plane of the cell.

518
00:43:56 --> 00:44:00
But, I think you'll start to see
the problem emerging at the moment.

519
00:44:00 --> 00:44:04
I think it's going to be this guy
right here.  I think a little arrow

520
00:44:04 --> 00:44:08
will probably appear before too long.
But what's happened is this one

521
00:44:08 --> 00:44:12
didn't get properly connected on
both sides.  But,

522
00:44:12 --> 00:44:16
the cell's going to go ahead anyway.
Watch.  The one up here is going to

523
00:44:16 --> 00:44:20
get pulled in.
There it goes.

524
00:44:20 --> 00:44:24
It's getting pulled in.
And then, once it's in there,

525
00:44:24 --> 00:44:28
then the cell is going to go ahead
and divide anyway.

526
00:44:28 --> 00:44:32
So you can see what the problem is.
This one's got to over here,

527
00:44:32 --> 00:44:38
and this one over here is missing it.
This process is known as

528
00:44:38 --> 00:44:43
non-disjunction.
This is the sort of thing that

529
00:44:43 --> 00:44:49
happens in cancer cells that have
broken, where the checkpoint gene is

530
00:44:49 --> 00:44:54
broken.  And then,
if you have that, then the cells go

531
00:44:54 --> 00:45:00
on.  The same problem happens in
meiosis, and it's up here.

532
00:45:00 --> 00:45:06
It's the same principle that if you
end up with, if you don't segregate

533
00:45:06 --> 00:45:12
the cells, the chromosomes correctly,
then you can end up with a sex cell

534
00:45:12 --> 00:45:18
that has two copies of one of them.
And the other one has none.  And if

535
00:45:18 --> 00:45:24
you have two copies,
or 2N plus 1N, then you end up with

536
00:45:24 --> 00:45:30
a trisomy.  And if you have zero
plus N, you end up with what's known

537
00:45:30 --> 00:45:35
as a monosomy.
So, these would be from defects in

538
00:45:35 --> 00:45:41
meiosis.  I'll just close by saying
the one that you probably have heard

539
00:45:41 --> 00:45:47
of is Down's syndrome which is
trisomy 21.  That comes about from

540
00:45:47 --> 00:45:53
this sort of process.
It's a very debilitating genetic

541
00:45:53 --> 00:45:59
deficiency.  Most of you are
probably familiar with it.

542
00:45:59 --> 00:46:04
This process happens.
Things go wrong at meiosis,

543
00:46:04 --> 00:46:08
about one in every [fifth?]
detectable human pregnancy doesn't

544
00:46:08 --> 00:46:13
go to completion for the most part
because of an underlying problem

545
00:46:13 --> 00:46:17
like this, that the body is set up
[to need?] the pairs of each

546
00:46:17 --> 00:46:21
chromosome.  If you have one too
many or one too few it's usually

547
00:46:21 --> 00:46:26
lethal.  So, if one in every five
human pregnancies has that happened,

548
00:46:26 --> 00:46:30
you end up with a miscarriage.  My
wife and I have been through it.

549
00:46:30 --> 00:46:34
It's a devastating experience.
I think you can just look around and

550
00:46:34 --> 00:46:38
figure the odds.
A significant number of the people

551
00:46:38 --> 00:46:41
in this room are going to have to
cope with this.

552
00:46:41 --> 00:46:45
And I'm just bringing this up for
your attention right now is it

553
00:46:45 --> 00:46:49
something that in our society we
tend not to talk about very much

554
00:46:49 --> 00:46:52
unless maybe you're a Hollywood
movie star and it makes it into the

555
00:46:52 --> 00:46:56
tabloids or something.
But it's a very common human

556
00:46:56 --> 00:46:59
experience, and very difficult to
cope with.  But there it is,

557
00:46:59 --> 00:47:03
for most of those pregnancies that
terminate very early,

558
00:47:03 --> 00:47:06
usually the underlying cause is a
problem and traces back to the kind

559
00:47:06 --> 00:47:10
of stuff we see here where something
went wrong during the segregation

560
00:47:10 --> 00:47:14
process of making the
sex chromosomes.

561
00:47:14 --> 00:47:18
And as I say, if it happens in just
our ordinary cells,

562
00:47:18 --> 00:47:23
that's one of the thinks that leads
the progression to cancer.

563
00:47:23 --> 00:47:26
OK, so I'll see you on Wednesday.