Just wanted to begin today by pointing out a couple of articles
from today's Boston Globe. There's an article that's on the
financial pages about investors reconsidering gene therapy,
and startups funded as technology evolves. A lot of you have heard
the words gene therapy. A lot of you, at the end of that
bacterial genetics lecture, said you weren't quite sure what
complementation was. But, gene therapy is basically
complementation but to work. The idea is if you got a broken
gene, and you can put in a good copy, then you'll take the cell back to
being normal, which is exactly what we're doing in those phage crosses
where we had two phage, one with the mutant copy of the gene,
and one with the wild type copy of the gene. And they're saying here
that there's a renewed interest. Now, the basic strategy in these
things is to take usually a retrovirus, the same kind of idea
that we heard about with the HIV-1 virus that will make a DNA copy,
and then the copy gets inserted somewhere in the chromosome.
So, the good thing is it puts and a new copy in a chromosome.
The bad thing is you got a piece of DNA being stuck somewhere in the
chromosome. And there are places where it can go where it doesn't
matter, and there are other places where it really does matter.
So, it's been a very tricky business with gene therapy.
Part of the thrust here is they're thinking that maybe they need to
pick targets were the person's going to die anyway so that if there is a
risk of getting cancer or something, it's outweighed by the possible
thing. That's sort of the thrust. You can see the article; it's in
today's paper. It's very timely for what we are
talking about now. And then on Friday I'm going to
start talking about recombinant DNA strategies and stuff.
But there's another article in today's paper.
This is one of those things that I told you about where an article is
published in the, in this case, online in the journal
nature. They have an embargo on a press thing until Thursday or so,
and then the article is on, the hot papers that have just come out show
up in the newspapers, usually either on Friday or Monday.
And this is yet another system that they describe as making a molecular
repair kit that corrects mutations in the cells' DNA.
So far, this has only been done in cells. But it's working well enough,
and the article is saying this approach could become a serious
competitor to conventional gene therapy. In here,
you have sort of a layman's account of this kind of complementation by
gene therapy. We're talking about gene therapy in that field which
attempts to force feed healthy genes into cells hobbled by defective ones
has been plagued by failure, and recently was found to cause
leukemia in some patients. That's probably because of the
insertion events associated with these viruses.
This new system rewrites the small stretch of misspelled genetic code.
That's typically the reason the gene has gone bad.
So it's a different kind of strategy. This is the first report
I've heard of that. Some of the stuff we're talking
about is sort of inescapable because you're going to see
it in the paper. Here, they're telling you the sort
of thing I was just saying. The viruses inject their payloads
at random within the cells tangled mass of DNA sometimes disrupting
normal genes. Even when genes land in good locations,
the molecular machinery that regulates their activity is also
often thrown off, leaving the healthy genes operating
at a level to low to be helpful or functioning in the wrong parts of
the body. It must begin to sound familiar. You stick a random piece
of DNA somewhere, you can disrupt the regulation in
the gene as well as just landing in the open reading frame.
So there's a problem with gene therapy. Now,
they'd like to make you think that this is going to be the promised to
everything, but as always it's more complicated. And so,
I just picked up the last paragraph of this article.
Other scientists said the approach looked promising,
but predicted it would end up struggling with this problem of its
own, James M. Wilson, a gene therapy researcher at the
University of Pennsylvania. Now, there's somebody who's in a
position to criticize, but also has a vested interest
himself and the alternative therapy, noted that the first step of the new
process causes for [zinc fingers?].
It's a kind of protein that's involved in this,
to make a fresh break in DNA to accommodate the insertion of the
corrected sequence. It's the same kind of break it with
radiation that can lead to cancer. And we're going to talk today about,
you'll see where double-stranded breaks and whatnot can be a real
problem in terms of the integrity of the DNA and genome stability,
which is maintaining gene stability so important in avoiding cancer.
You guys are a tough crowd. Comments ranged from, this was the
best lecture that I'd given to ones that were absolutely the other end
of the spectrum. You're a very hard group.
I truly am going to take, I don't have time really to sit back and
redo all my lectures, but I've a huge amount of input,
and I'm going to go back over all this input and getting,
and take it very seriously in terms of how I go about things next year.
I can see a number of changes and going to make.
Whoever sent me the e-mail that talked about the Dock Street
Bohemian Pilsner brewed in Utica, NY, this classic golden Pilsner,
pungent, perfumy taste and so on, it was a moment of lightness, but if
I got to many things like that it's not going to hell in a contract to
figure out how to do. For the person who asked about how
to avoid accidental pollination, when they're going to do that, they
actually take the stamens off the flowers so you don't get accidental
self fertilization. You actually go out and make ones
that are just male or just female flowers. You can do that rather
easily. OK, so what we got into last time, or what I told you last
time, and I promise you that there's another Mendel lecture coming.
For those of you who thought this was a little slow,
you may find the next one is all too fast. But anyway,
that will be how it goes. Mendel had carried out this
fundamental series of experiments. And I did linger over it because I
think it's so simple you can actually see the scientific process
in action, and it also isn't complicated by any techniques that
we can't see. And it was a tremendously important insight that
genetic information came in units. But as I told you,
it wasn't accepted because for most of the world at the time,
it was a statistical argument. There weren't any entities that
were two of inside a cell, and all that sort of thing.
So, it didn't take over scientific thinking. It wasn't until about
1900 when several other geneticists did finally find the systems that
duplicated Mendel's results, and therefore showed that these were
general inferences, something that Mendel himself,
as I told you, by choosing weeds and bees as follow-up systems
hadn't been able to do. These other geneticists showed them
in other systems. But the other thing that made the
difference at the time, was by this point cytologists,
who were looking at cells under microscopes, had found entities
whose behavior seemed to match those of these particles of information
that Mendel had postulated to explain these patterns of
inheritance that he was seeing. These particles,
because they were called chromosomes, which literally means colored things,
the reason they were colored was not because they were inherently colored,
but because cytologists were staining the cells with a variety of
things. And that was what allowed them to visualize these.
And so, by staring into microscopes, right around this time, around the
turn of the century, 1900s or so, cytologists had come up
with three key observations. One was that chromosomes came in
matched pairs. So, let's say in this cell,
there were too long and too short. So that's a chromosome. And a
correspondence, we now know, to double-stranded DNA
molecule that's been all condensed up.
And there are two copies of each chromosome in this thing.
So: too long, too short, one came from mom, one came from dad.
And for bookkeeping purposes, I'm going to color them so that from
one parent is unshaded, and the other one is shaded.
Most of you know in human cells we have 23 pairs of chromosomes.
This is a now fancier method of visualizing chromosomes called
[peating?] chromosomes where you take little stretches of DNA that
are unique to particular sequences, attached dyes, and then use them to
[stain?] the cells, and so they will color only
particular chromosomes. And we have 22 pairs of identical
chromosomes, and then the sex chromosomes here,
X and Y, this would be a male, or two Y's if we were female.
We'll return to those in the next lecture. Kim Naismith,
who spent his life working on how these chromosomes segregate gave a
talk a year ago. He's in London at a hospital in
London. And then he brought in the next slide. There was an artist who
spent several months visiting with him, trying to find ways to
represent in art some of what she saw going on. And I thought you
might enjoy seeing this, the slide. This is the human
complement of chromosomes, represented in stripy socks that
various staff members from the hospital brought in for
her to do this. So, a little touch of scientist
humor which some of you may think is pretty nerdy, but anyway there it
was for what it's worth. He showed that in our departmental
[colloquium?]. OK, the second thing,
then, that the cytologists noted by staring at this was during ordinary
cell division, which gives two identical daughters
the numbers of chromosomes per cell is preserved.
And this ordinary cell division is
given a special name of mitosis. So if we take this cell, the first
thing that happens, then, is the chromosomes are
duplicated. We've talked a lot about DNA
synthesis at the molecular level. This is looking at it. Excuse me,
and so, there are now two DNA molecules, that each one of these
new DNA molecules is given a special name.
This is called a chromatid. So there was one DNA molecule here.
It's now duplicated, but you'll notice these are still joined
together. The point at which they are joined together is known as the
centrosome. And then, after this, after the DNA's been
copied, these things are lined up at the center of the cell and then they
are pulled apart to give two daughter cells that are just like
what you started with. This part, so this is 2N,
if N is the number of kinds of chromosomes. And then there's two
each. This is 2N. At this point, the DNA contents of
the cell is 4N. This is 2N. This is 2N.
We're back to where we started. This part was invisible to the
cytologists, at least in the sense the chromosomes at this point are
extended. And so, they weren't able to visualize them
by looking through the microscope. But as it came time for cell
division, then the chromosomes condensed up very tightly.
This is probably to avoid tangles. And you need to pull them apart
into the two daughter cells. And then the part that could see
them, this was known as mitosis, this process by which the
chromosomes are pulled apart. So, mitosis is a mechanism for
nuclear division that results in two daughters with identical
genetic information.
When you contrast this to meiosis, which I'll show you in just a minute,
this has been studied for years in a kind of observation way.
I showed you at some point. This is an animal cell where the
chromosomes line up, and then they pull apart.
I think I showed you, and you can see the cells divide once they've
done that. I'm going to show you this next thing,
which everything happens more slow motion. This is a picture of the
blood lily, so it's a plant. Again, the choice of model system
is often, if it has a feature that is good for a particular thing.
This happens, very easy to visualize in these lily cells.
Now here, the cells have duplicated their chromosomes,
and the daughter chromosomes are held together.
They're glued together, so you can tell in this thing that
they've been glued. Now, in order to separate the first
thing they have to do is line up at the equator of the cell.
And then it pulls apart and you can see that each daughter cell gets one
of the duplicated chromosomes. OK, so that's mitosis.
It generates two copies of what you started with. The other observation
that the cytologists made was that cell divisions that produce sex
cells work by a different system. So, the third thing,
And, I'm going to give you the
scientific word now for sex cells. So, they're usually called gametes.
General term, so that would be sperm and egg,
or pollen would be a kind of gamete.
In this process, the number of chromosomes is halved.
And this special type of cell division is known as meiosis.
It's very important, because if we didn't have meiosis we wouldn't
have any progeny. We need to be able to cut the number
of chromosomes we have per cell in half, so as Mendel inferred,
then when each parent made a contribution you'd be back up to the
right number of cells. Now, so this process begins again
by duplication of the DNA. So this would be 2N.
Now we go to, as before, with one interesting difference here.
So we are at 4N in the cell.
But you notice that drawing these duplicated chromosomes with
chromatids overlapping. This point of, I didn't do this too
well. The point of connection: what are the two chromosomes overlap is
known as the chiasma. It's a point of actual physical
interaction between the chromosomes.
And what it allows the cell to do is to have the two homologous
chromosomes, in this case the two long ones, find each other,
and actually physically interact. That's a critical event for the
next step that I'm going to show you. It's also a point,
which you'll see in the next lecture. There is additional genetic
diversity introduced into the system.
So, at this point, what's happened is that the DNA has
doubled, at this point, looks sort of like mitosis except
for the fact that the duplicated chromatids have overlapped.
There's a least one of these for every pair of duplicated chromosomes.
So what happens in the next phase, which is known as meiosis I is that
the pairs of duplicated chromosomes are separated.
So, we get two cells. We might get, say, the unshaded of
this one and the shaded of the little guys. And the other one then
is shaded with a long one, and shaded with this one. This is
2N, and this is 2N. But if you'll take a look at what's
happening over here, you will see that we don't have the
same thing going on. In that case, we were producing
identical copies of the starting cell. In this case,
we've got something different now because we've separated both copies
of, let's say, the chromosome from dad from both
copies of the chromosome that originated with mom,
and the other way over here. These, then, undergo a second round
that's known as meiosis 2, which resembles now mitosis in the
sense that the duplicated chromatids are now pulled apart into daughter
cells so that this one will generate what long, unshaded one,
one short, and there will be two of those. In the cell,
it will generate a shaded long and unshaded like that.
So now, there are four of these. And you'll notice that there is now
an N. So, we have the number of chromosomes during meiosis via a
process by two rounds of division. The other thing you can think of is
you can begin to see, at least, when the evolution of sex
was such a powerful force in driving evolution by introducing so much
variation, because each of us has a copy of each of our 22 chromosomes
where we have homologous pairs, one from mom, one from dad.
That every time we make a sex cell, a sperm or an egg, what happens is
for chromosome 1, you can either get a copy from mom
or the copy from dad. And then the next one: copy from
mom, copy from dad, and so on. You can see the variation is
possible just from that part of the process alone.
And there's going to be more variation that come about from
events that happen where this chiasma is as I'll show you.
So, meiosis then, as I said, is a mechanism for nuclear division
that produces four daughter cells with half the genetic info
of the original. So, how did I write that?
And in this case,
the daughters are not identical. Does somebody have a question?
Yeah? Oh, this part of the process,
the cytologists broke this down when they were observing.
So, it was a part they couldn't see. When they started to be able to see
it, they first saw this one division, and then the second division.
They called the first round or division of meiosis 1, and
the second meiosis 2. So it was just a name given to the
process. Yeah? Oh, sorry, excuse me,
I see the problem. OK, it goes this way. This period of
time is called meiosis 1. That part of the process is called
meiosis 1, meiosis 2, sorry. Yeah, I mean what I wrote down as
arbitrary. You could've had to for mom, and two from dad.
And in fact, I guess if we have 22 pairs we could eventually have a
sperm or egg that had all of the copies from mom, and all
of the copies from dad. You could calculate the statistical
chances of that happening, but what you'll discover as we'll
find next time, is that even if you did that the
chromosomes would no longer be identical to what you got from mom
or dad, because there's a little bit of genetic recombination going on
during that process. I'll also show in a minute that you
can get errors in this process, and that these are important.
So, what happens then is that fertilization,
what the cytologists can see happened was that the number of
chromosomes have been halved. So, you had N plus N giving you 2N
where this might be, for example, the egg,
and this might be the sperm, since gametes have half the number
of genetic content when they fuse, then you go back to the original
number. And this gave rise to what was known
as the chromosomal theory of inheritance. Even though
cytologists didn't know what these colored things were,
they seemed to have the properties that you would expect the carriers
of the genetic information to have. Be duplicated before a cell was
going to divide and then they seemed to be very precisely segregated so
that each daughter cell got one copy. And it made sense,
then, in terms of the formation of sex cells you'd have,
and then it would all come back up. So, the cytologists proposed this
chromosomal theory of inheritance. Chromosomes were the carriers that
carried the genetic information. And you can see now that Mendel's
work was rediscovered, which is more or less what happens
around 1900, how beautifully it mapped on top of this because the
genetic information came in particles. You'd think,
oh, well those particles are sitting on those chromosomes.
They get duplicated. They get separated. They get divided in half.
Their number gets divided in half when you make sex cells.
So, I want to at least point out, let me go onto this next thing here.
Here was one other picture I'd shown you. This was a cancer cell
dividing again. We see the same process at work.
And that just reminds you, when I was talking about that kind of
process, trying to remind you that one cell gives rise to two cells,
and one DNA molecule gives rise to two DNA molecules.
But these phenomena are related [even no one tends?
to talk about in different parts of the courses, and if you've got more
than one DNA molecule per cell, then each one's a chromosome. And
then you have to take care of segregating those as well.
But a point that I'd made is that up until this part at the right
could be a yeast or an E. coli, but if it's going to be
someone, something more complicated that's got different kinds of cells
like us, then we have these ultimately, an adult human
with 1014 cell. So, this process has happened over,
and over, and over again. And it has to be really very accurate.
And, there was remarkable advances have been made in understanding this
process over the last few years. And a lot of this was due to the
work of Lee Hartwell, who carried out experiments,
I guess, that offered some key insights into the basis of the whole
cell cycle, of which this is just part. So they said,
here we can't really see all of this stuff in the microscope.
What cytologists were able to observe was that after the
chromosomes had duplicated, then they condensed up. They became
visible, and they could see that part of the system.
So, a great body of knowledge has been learned over the past few years.
Lee Hartwell, who was a postdoc at MIT with Boris
Magasanik a number of years ago, was one of the key people who led to
this round of insights. And what we now know, the cell
cycle can be basically divided into four parts.
So a newly born cell, if you will, undergoes what's known
as phase of the cell cycle that's known as the G1 phase.
And you could think of this as, amongst other things, sort of
preparation for duplicating the cell's DNA. And then,
there's a phase known as the S-phase, which is what DNA synthesis
takes place. That now gives the cell and
information content of 4N. There was then another phase known
as G2, which you could think of as preparation for pulling the
chromosomes apart, and for the cell dividing.
And that's known as mitosis. And so, this is quite remarkable.
It's quite fundamental. It's a very elegant and very complex system
of controls. And what Lee learned is that there is an elaborate system
of what we now know as checkpoints in the cell cycle.
And the idea is pretty much the same sort of thing that you might do
if you were an engineer and you were setting up a quality control process
that involved a series of stages. And what a checkpoint does is it
basically commands successful completion of a prior phase before
the system is permitted to move to the next stage.
And you can sort of see the problem here, that if you are trying to,
say you're copying your chromosome, your DNA, and you only got part way
through. And then he proceeded to the part where you pulled the
chromosomes apart. There would be all kinds of chaos
inside of the cells because you would be breaking chromosomes.
You wouldn't be getting identical information. And there are three
major checkpoints. There is a checkpoint at the G1 S
boundary. There is actually more than one. But there's an intra-S
phase checkpoint, and then there's another one at the
G2 M boundary as well. And the way that Lee found this out,
I wanted to just take you back because remember when I was talking,
well, first we talked about how would you get an mutant affecting an
essential cell, a gene whose function is essential
for the cell. [He said? you'd have to be conditional in
some kind of way, because the organism would be dead,
and couldn't use genetics to study it. So, when I introduced you to
those phage, and we wanted to study critical functions needed for phage
growth, we needed a conditional mutant. Remember,
we did look for temperature sensitive mutants.
So that's what Lee Hartwell started to do with yeast in 1970
approximately. He just looked for mutations that
were temperature sensitive lethals in yeast.
Now, yeast can be diploid, but they also can be haploid,
which is just one copy of genetic information. So just like the
bacteria [haploid yeast? , if you get a mutation affecting a
gene, then you see its phenotype right away because there isn't a
complication of the second chromosome. And Lee got the Nobel
Prize for his work, just, I forget, three years ago or a
short time ago anyway. And so, this was the process he was
studying. I showed you this movie.
In this case, this is budding yeast, and you can see why it's called
budding yeast is that rather than the still growing and segregating
down the middle, the daughter cells grow as little
buds coming off the side. The DNA is still going to be
duplicated as we got, and then segregated into the
daughter. So that part of the process is there,
but there's yeast growing sped up a bit so you can see it.
So, what we found was that when he looked at his TS mutants,
he found that they tended to arrest at characteristic stages,
and he was able, then, to figure out that there must be some sort of
checkpoint system that is something went wrong during one of the faces,
then the cells with all pile up at a particular characteristic stage in
the cell cycle. And this was controlled by these
checkpoints. These checkpoints are of enormous
importance because if something goes wrong with them,
as happens often in cancer cells, then you get a huge increase in
instability of the genome very similar to the way,
using, for example, mismatch repair causes instability of the genome and
therefore things that can cause a cell to forget to divide when it
stopped dividing when it hits its neighbors, which part of the cell it
belongs to and so on. Those kinds of changes will come
with much greater frequency. Another thing that was completely
remarkable was because it was yeast it was relatively easy to find genes
that were broken. Going back to complementation,
leaving aside the technicalities, if we had a mutant that's a TS
lethal and it's dead, if we put a good copy we'll know it
because the cell won't die at a high temperature anymore.
So, you can sort of see from the first principle it was relatively
straightforward to find the genes in yeast that are necessary for cell
cycle control. The remarkable thing is that
they've been concerns all the way up to humans that the proteins that are
involved in the cell cycle control are virtually identical in humans.
So, the system, again, is probably locked into place because it works
so well. And once it was working, then evolution didn't have a lot of
space. I won't say it's completely identical in human cells,
for example, have a few more wrinkles that they throw away.
And fundamentally, you can see evolutionarily that the
system [involved once? . One thing I just want to comment
on, and here's just an example of the sort of thing that can happen if
you get a problem with pulling chromosomes apart when they're not
ready, or something happens that make a break in a chromosome.
You will get a double strand break, and cells don't like that, and they
try and fix it up. I think in this case,
you can see the chromosome 9 has picked up a piece of a couple of
other chromosomes. This piece here came from
chromosome 8 over here, and this piece here came from
chromosome 22. And so, this cell now has things
kind of messed up. And this particular chromosome's
got parts of two other chromosomes. And so, you can start to think
about the consequences of that. You'll see when you start
segregating chromosomes, there are issues. And also,
the junctions themselves can sometimes do things like creating
fusion proteins that have aberrant properties, for example,
a signaling molecule that's now locked permanently into the on
position or something like that. Those sorts of things can happen by
these as well. So, here's a very abbreviated form,
the principal that happens, or what happens so that the chromosomes
become visible in the microscope. There is about a couple of meters of
DNA in every human cell. So, you can see almost from first
principles, it almost has to be packaged in some way to fit in that
little, tiny area. And down at the basic level,
the DNA is looped around a little cluster of proteins called histones.
And then, as the cells approach the mitotic stage,
they package these and higher, and higher, and higher levels of
packaging so that the chromosomes get more and more compact,
and therefore less like spaghetti, and less likely to get tangled when
they are pulled apart. Now, this teaching as part of the
course. It's in the book. It's a little like glycolysis,
though, and there's so much detail. It's hard to notice at all. And
what I've tried to do here is just sort of take a step back,
focus you on the really big parts of the process.
But you can see this is a sort of typical textbook thing showing you
the various sub stages of this process that cytologists have given
names to each part of this. For example, you can see the
chromosomes lining up at the equatorial phase just before they're
going to be pulled apart. One little detail which I glossed
over at this point as you can see that the chromosomes are,
of course, surrounded by the nuclear membrane.
And, at least in many cells, what happens is just before the
chromosomes are going to be pulled apart, this nuclear membrane in a
matter of 20 or 30 seconds goes from being a membrane into sort of
breaking into a whole little series of membrane sacs.
And then, after the chromosomes have pulled apart,
now you reassemble the nuclear membrane around each set of
chromosomes. And I think there's still an awful lot to be learned
about how that particular trick is done. And that's a
textbook diagram. These are the kinds of things the
cytologists were looking at as they were describing it.
And one thing you can certainly see, I think, is that there are a lot of,
if you want to think of them as cables, this whole process is done
by molecular machinery. And in fact, one of the key things
for ensuring that the chromosomes are all lined up is each are
attached to each poll of the cell. So, an individual chromosome feels
tension on both sides, and there's pretty good evidence at
this point that says that what has to happen before mitosis is allowed
to proceed is that each duplicated chromosome must feel the tension on
both sides. And if one of them is only attached on one side,
it's not allowed to go ahead. Here are a couple more pictures.
The chromosomes are in blue, and all this cabling is in green.
You can see a molecular machine's basically at work.
And I wanted to show you this picture because this is important.
There's two parts to this. Julie, could you hit? So, this is a normal
mitosis. These are in lung cells from a newt, which are very flat.
So it's easy to visualize them. I believe this is by Nomarski, a
kind of optics called Nomarksi optics. What they're doing,
the duplicated chromosomes are getting lined up at the equatorial
position in the cell, and you get a spindle attached to
one side, and then a spindle attached to the other.
And once that's happened, then you can see the chromosomes.
Watch this one over here, for example. It just got attached,
and it's being pulled into the middle.
And once the cells feel that all the attention, there's tension on all of
them, and then it enables the next stage of the process.
And you will see each of the daughter chromatids segregate before.
And, I just want to impress upon you it's complicated enough just
replicating the DNA at the [fidelity? . We talked about an awful lot of
other stuff has to go on. And it would be a reasonable
question: is there ever a mistake? And there is. This one actually
shows another cell where there's going to be a mistake.
You can't see it yet, but you can see the chromosomes are all
condensed up. And they are beginning to get these spindles
attached. And as they get attached to the site then they get localized
in the central part right down the equatorial plane of the cell.
But, I think you'll start to see the problem emerging at the moment.
I think it's going to be this guy right here. I think a little arrow
will probably appear before too long. But what's happened is this one
didn't get properly connected on both sides. But,
the cell's going to go ahead anyway. Watch. The one up here is going to
get pulled in. There it goes.
It's getting pulled in. And then, once it's in there,
then the cell is going to go ahead and divide anyway.
So you can see what the problem is. This one's got to over here,
and this one over here is missing it. This process is known as
non-disjunction. This is the sort of thing that
happens in cancer cells that have broken, where the checkpoint gene is
broken. And then, if you have that, then the cells go
on. The same problem happens in meiosis, and it's up here.
It's the same principle that if you end up with, if you don't segregate
the cells, the chromosomes correctly, then you can end up with a sex cell
that has two copies of one of them. And the other one has none. And if
you have two copies, or 2N plus 1N, then you end up with
a trisomy. And if you have zero plus N, you end up with what's known
as a monosomy. So, these would be from defects in
meiosis. I'll just close by saying the one that you probably have heard
of is Down's syndrome which is trisomy 21. That comes about from
this sort of process. It's a very debilitating genetic
deficiency. Most of you are probably familiar with it.
This process happens. Things go wrong at meiosis,
about one in every [fifth?] detectable human pregnancy doesn't
go to completion for the most part because of an underlying problem
like this, that the body is set up [to need?] the pairs of each
chromosome. If you have one too many or one too few it's usually
lethal. So, if one in every five human pregnancies has that happened,
you end up with a miscarriage. My wife and I have been through it.
It's a devastating experience. I think you can just look around and
figure the odds. A significant number of the people
in this room are going to have to cope with this.
And I'm just bringing this up for your attention right now is it
something that in our society we tend not to talk about very much
unless maybe you're a Hollywood movie star and it makes it into the
tabloids or something. But it's a very common human
experience, and very difficult to cope with. But there it is,
for most of those pregnancies that terminate very early,
usually the underlying cause is a problem and traces back to the kind
of stuff we see here where something went wrong during the segregation
process of making the sex chromosomes.
And as I say, if it happens in just our ordinary cells,
that's one of the thinks that leads the progression to cancer.
OK, so I'll see you on Wednesday.