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The following content is provided by MIT OpenCourseWare under a creative

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commons license. Additional information about our license and

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MIT OpenCourseWare in general, is available at ocw.mit.edu The

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end of last lecture I got an interesting question about apoptosis

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which I covered very briefly towards the end of that lecture. And the

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question was this: Do healthy cells tell sick cells to die?

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Or in turn, do sick cells tell healthy cells to die?

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So, is there some kind of communication between cells as to

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who is healthy and who is not healthy? For those of you who are

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just coming in, there is a handout outside,

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and up front, it's the same thing. And that's actually a very

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interesting question because they really does seem, in the body, to be

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some sense of monitoring whether cells are healthy or not.

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Now, a lot of the time, cells that are not healthy

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intrinsically activate their own death program,

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or they have the ability, they gain the ability to respond to

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some kind of extrinsic signals. And in fact, signals could be sent both

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ways, we believe, where sick cells will tell healthy

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cells to die under conditions that are obviously not favorable to the

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organism, but more important, that healthy cells can tell sick

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cells not to survive. So, the balance of apoptosis and

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cell survival is a very delicate one and regulated by many,

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many things. So, it's a good question. All right,

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we move on. We move on to a new module. So, you have, in fact, covered

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the foundations of modern biology. You've covered them in a very

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superficial way. And I want to emphasize that. You should,

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by now, know how to take a piece of DNA, conceptually turn it into RNA,

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and conceptually turn that into a protein. You should know what to do

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if the DNA sequence is changed. You should have the expectation that the

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RNA and protein that are made from it will be changed,

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too, and you should have various other nuggets of information that

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are covered by foundations. These foundations are not going to

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go away. We're going to use them throughout the rest of these

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uncovered black boxes. And I'm going to assume that you

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remember a bunch of stuff as I go through the material in the next

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several lectures. But we are going to move in to the

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formation module. And today, we are going to talk about

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things in a kind of overview way. And I'm going to tell you five

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major things that are important. And I'm going to write them on the

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board, and some of the things they need to know about them. And

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we will use the slides as well. So, what is formation? What is this

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module all about? Well, it's about something called

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"development," where development is the process by which one cell,

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the fertilized egg or the zygote goes on to make a multi-cellular and

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complex organism.

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This is not about squishy little embryos. OK, this is about life as

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it began, as it continues in your own bodies.

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And it has immense applications for multiple biomedical and

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bioengineering processes that I'll talk about as we go through. The

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first thing you need to know is what's written up here is that the

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development occurs over time and space.

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And that's one of the things that makes it an incredibly complex set

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of processes to think about. The overtime can be a long time. And

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what's important to understand is that developmental processes occur

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throughout life. Initially, in the formation of the

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organism from a single cell, the fertilized egg, the zygote,

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and later on, early in the formation of the embryo,

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and later, in the renewal of the adult.

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And this is where the stem cells come in. And

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we'll have a lecture on stem cells later on. But

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development is something that occurs throughout life. And

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in fact, I teach an upper-class course on development to graduate

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students. And the first thing I tell them when I

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start to teach them is really there is no such subject as developmental

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biology because it covers, it includes, it encompasses

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biochemistry, genetics, molecular biology, protein structure,

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and many different disciplines. And it occurs throughout life. So,

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it really covers everything. But we have put these things together in

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the formation module, and I think you will find them

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interesting. OK, so here's a schematic of how things

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work courtesy of Picasso. And really, this whole process is quite

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remarkable. It starts with two dying cells.

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The egg and the sperm, haploid cells that have a half-life

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that have a life of about 12 hours up to which they are dead. But

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when they fuse, there's magic that happens, and you get a viable cell,

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the zygote, that has the capacity to go on and divide many,

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many times to form an embryo and ultimately an adult organism. And

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as we've mentioned many times, it is estimated that there are about ten

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to the 14th cells in the human. In the adults,

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and even in young adults, there is much replacement of cells

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throughout life. And this whole process obviously takes place over

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time. But that's important because the time component means that things

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change over time. And in order to understand this entire

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slide, you have to factor in this fourth dimension.

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So, what are some of the things that we're going to cover in this module,

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and why are we bothering to talk to you about the subject?

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Well, one of the things that's of interest is the effect of chemicals

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on the formation of a normal body. So, there are these things called

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teratogens, which are chemicals that affect formation of early steps in

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development of the embryo. This is a famous one, the effects of a

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famous one called thalidomide that was given as an anti-nausea

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medication during pregnancy some decades ago.

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It has no effect on rodents on which it was tested,

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but it was not tested on primates before you give it to people,

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and it has the devastating effect of preventing limb formation,

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and a number of people were born in the late 1940s,

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early 1950s, who lacked limbs because of the effect of

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thalidomide. And I have to tell you,

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this is very interesting for those of you who are interested in

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chemistry. Thalidomide has a pretty simple chemical structure. It has

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been studied for many, many decades. It's a very interesting drug because

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it turns out it prevents cachexia, which is the wasting that occurs

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with many disorders including HIV-AIDS infection. So,

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thalidomide is a very, very useful drug. It has a simple chemical

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structure. It's been studied for decades, and we do not know its

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mechanism of action. OK, here's another one that you might be

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familiar with, the drug, not the syndrome, I hope.

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So, fetal alcohol syndrome, so, a normal brain, this is a brain

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taken from a fetus. That is the late stage gestation human whose

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mother drink excessive amounts of alcohol during pregnancy. So,

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during the early stages of pregnancy the first few months,

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alcohol is devastating to formation of the brain and also to the bones

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of the face. And even a reasonable number of drinks,

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apparently, just a few can significantly lower the IQ points of

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a baby. And so, it's a good reason not to drink if

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you're pregnant. This was a very devastating case.

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You can see the brain is very smooth. It doesn't have those nice

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valleys and hills, the sulci and the gyri,

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that the normal brain has, and this fetus would not have been able to

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survive. Here's one. This is the dream of all biologists,

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developmental or otherwise. It's a dream of bioengineers. It's

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probably the dream of everybody. Someone cuts off their arm in an

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accident: can we grow a new one? Well, newts can. So, in this

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example, newts can. So, in this example, the newt limb,

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this poor animal was amputated just above the elbow. But over a period

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of a few months, another limb grew back,

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smaller than the original but perfectly functional.

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We can't do that. How do newts do it,

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and how could we use that information to help people grow new

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limbs, or new hearts, or new eyes? Fish, for example,

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the fisheye work on zebrafish can grow a new heart. You can cut the

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heart into two. Take away half of it. It'll regenerate a new heart.

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There are animals were you can remove half of the retina or all of

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the retina, and it will regenerate a new retina. We do some

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regeneration. You can take away two thirds of the liver, and new

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liver will grow back. And that's one of the principles

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behind liver transplants. But we can't do things like regenerate

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eyes, and hearts, and limbs. It's been the focus of

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study for a long time to try to figure out how newts do it,

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and to ask whether we can capitalize on that knowledge. And

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I have to tell you, it's been a very tough area of biology,

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still wide open. And that's where the great god of stem cells comes

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in. Because it's been so difficult to get limb regeneration,

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for example, and heart regeneration, there is a sense that perhaps we

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could get groups of cells to repair damaged organs.

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And stem cells are the things that hold this promise. And

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we'll have a whole lecture on this later. And part and parcel of stem

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cells is the very newsworthy issue of human cloning,

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making identical replicas of things. And we'll talk about this also in

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a separate lecture. OK, all right,

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so let's move on to the next set of things that you need to know. And

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that's the notion that there are multiple processes that are involved

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in setting up development formation of any multi-cellular organism.

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So, multiple processes are involved. And these are cell division,

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right, a single cell, so, ten to the 14th cells. You figure out how many

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rounds of cell division at us. Actually, that's a tough question.

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You could go and do that, OK, and over spring break if you're

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lying on the beach or hanging out on a mountain, if you can find any snow

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you can go and figure out how many cell divisions it takes to get ten

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to the 14th cells. But it's not so easy because cells

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don't just divide from one to ten to the 14th. As they are dividing,

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there's a balance of cell division, and as we talked about last lecture,

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of cell death. OK, so cell division versus cell death,

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and so I can't tell you how many divisions that takes because there

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are a lot of cells that die along the way to those ten

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to the 14th cells. Here's another one: cell type.

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What's cell type? Different kinds of cells in the

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body, we mentioned this right at the beginning of the course. Skin cells,

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cells that produce the hair, nerve cells, red blood cells,

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and so on. There are probably 500 different cell types,

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and these each have specific functions. And

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the definition of a cell type really is a group of cells with

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a particular function. Something else that's interesting

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about turning that single cell into a multi-cellular organism is the

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notion of position. So, if you look at yourself in the

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mirror with all your imperfections, you likely have your arms coming out

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of your shoulders, and your head coming up above your

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shoulders also. Something has made the decision to put those parts of

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your body in their correct place. And that system is a set of

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positional information. It's kind of like a map. And as you're going

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from a single cell to a multi-cellular organism,

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there is a set of molecular information that really puts the

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coordinates on a map just as it you had a blank map of the world and you

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put on the Cartesian coordinates. So you would do that to the

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developing embryo. So, there's something called positional

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information, and the final thing is three-dimensional structure.

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And we'll have a whole lecture on 3-D structure. But

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suffice to say for now, cells do not work as single

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entities. The blood subsystem, the hematopoietic system, is the

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only real example in the body of cells working as single systems.

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And even there, they don't really. In all cases,

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cells group together to form tissues, and is tissues grouped together

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to form organs. And the precise three-dimensional

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structure by which they form is really important. So,

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here are some examples. I'm going to show you a movie of some stages

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of human development. This is taken from material collected a long time

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ago. And what I want you to see is that over a period of a few weeks

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how the sides of the embryo changes due to cell division. OK, so --

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 So these are all taken at the same

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magnification. And you can see that as time progresses,

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the size of the embryo changes, and this was all due to cell

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division. You can see that shape changes as well,

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and this is due to various processes including modeling through cell

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death. One of the interesting things about this,

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and this will be on your website. You can look at it.

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One of the interesting things about this is that early human embryos

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have a tail. So, you had a tail, a really pretty good

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tail until you were about 56 days old. And then,

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it disappeared. And in these early embryos,

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if you go back and look at this again, you will see the embryo has a

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tail. So, this is a manifestation over the tremendous change in size

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of a human embryo caused by changes in the number of cells. This cell

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death, duck feet, chicken feet, chicken feet are not

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web. Duck feet are webbed. They start

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off looking almost identical. And the difference is that between the

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digits, between the fingers or the toes, the cells die in the case of

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the chicken, and they do not die in the case of the duck. And

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if you go back and look at this, you will see that there are little

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dots between the digits of the chick, and not the digits of the duck,

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and those are the cells dying. So, there is a controlled process of

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cell death that's very important. Tissues, cell type,

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this is really one of the most extraordinary examples in the body

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of different cell types, and different cell types working

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together to a common function. This is a diagram of the retina that I

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took from your book, and it exemplifies two things: one,

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a bunch of different cell types. These are all nerve cells that are

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in the retina, and they are nerve cells that in

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various ways, either sense light or transmit the signal of the light

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once the light has been sensed to other nerve cells.

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You can see, firstly, there are these different cell types,

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and you can see secondly, represented by colors, you can see

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that they're organized in layers. There is a very precise and very

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important layering of cell types in the retina. If you disrupt that

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layering, the retina doesn't work. And in many cases of retinal

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degeneration, the retina doesn't work because the cells have,

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the layering has been disorganized, and the cells can't make the proper

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contacts with one another. Position: we talk about axes in the

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animal, and in the adult as well. We talk about an anterior,

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posterior axis, which is the set of organs from the head to the tail.

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We talk about a dorsal, ventral axis from the back of the

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animal to the belly. And we talk about a left-right axis from

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the left to the right. So, if you look at yourself in a mirror

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again, you'll look pretty symmetric. If you were to peel back your body

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wall and look at your organs inside, you will see that you are not

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symmetric at all. You have an asymmetry along your left-right

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axis. OK, so you will need to know these terms: anterior,

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posterior, dorsal, ventral, and left-right is easy. And

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finally, here's three dimensional structure. Here is the heart.

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The heart is a muscle. It's actually got several different cell

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types. But it is mostly muscle where the muscle is arrayed in

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various, precise, organization. And

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it's this precise organization of the cells that allows the heart to

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pump. How do you get this organization? We'll talk about that

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later on in the course. Can you regenerate this organization either

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artificially, or in some kind of tissue culture system?

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Very tough to do, and as you may know, there is no good artificial

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heart out there right now. This is a great thing for some of

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you to think about for your future careers. It's wide open. Are there

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circumstances where we could regenerate a human heart in a test

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tube or in a large test tube on a Petri plate, for example?

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It would have to be a very large test tube, right,

262
00:20:22 --> 00:20:26
a box, a test box? I don't think so. I think that is

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really going to be very, very tough to do, and I think we

264
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have to think more carefully about how we are going to repair

265
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damaged hearts. Again, we'll talk more about this.

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00:20:36 --> 00:20:40
So, what I'm going to do now is to show you a movie of the development

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of an early fish embryo. The kind of fish is called a zebra fish. I

268
00:20:44 --> 00:20:48
work on these in my laboratory. I have about 10,

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00 of them there, and I'm going to use them. Yes,

270
00:20:52 --> 00:20:56
I have 10,000 fish. If you want to come and visit my laboratory and see

271
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my fish, you can. It's a fantastic model system.

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00:21:00 --> 00:21:04
And I'm going to use this movie and this embryo to show you something

273
00:21:04 --> 00:21:09
about the sequence of events that take place during development. I

274
00:21:09 --> 00:21:14
want you to look for cell division, and I want you to look for

275
00:21:14 --> 00:21:19
structural changes as you watch the movie. Let's look at the movie

276
00:21:19 --> 00:21:24
again without the music. And let me show you what you're looking at. So,

277
00:21:24 --> 00:21:28
to zebra fish, like the chicken,

278
00:21:28 --> 00:21:33
and actually almost like the human develops as a disk of cells,

279
00:21:33 --> 00:21:37
or from a little disk of cells. I'll show this to you again when it

280
00:21:37 --> 00:21:41
starts again, that sits on top of a yolk cell. Chickens have got a yolk

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00:21:41 --> 00:21:45
cell. That's the yolk of egg. Humans don't. But otherwise things

282
00:21:45 --> 00:21:49
are very similar. Let me try to start that. OK,

283
00:21:49 --> 00:21:53
good. So, we're going to look at this again. Here is the yolk cell.

284
00:21:53 --> 00:21:57
This big round ball here is the so-called yolk cell,

285
00:21:57 --> 00:22:01
and that's going to be the food of the embryo. These two bumps

286
00:22:01 --> 00:22:04
on top are two cells. This is a two cell stage embryo.

287
00:22:04 --> 00:22:07
And as you watch the movie for the last time, and I'll post it on your

288
00:22:07 --> 00:22:11
website so you can watch it as much as you want, you'll see these two

289
00:22:11 --> 00:22:14
cells divide into four cells, and eight cells, and 16 cells,

290
00:22:14 --> 00:22:17
and so on, until they've made a little dome of cells sitting on top

291
00:22:17 --> 00:22:21
of the yolk cell. And then, at that point, suddenly at some

292
00:22:21 --> 00:22:24
point, and this is very interesting. That group of cells realizes that

293
00:22:24 --> 00:22:27
there's enough of them, and they start to move. And they

294
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spread out to cover the whole yolk cell.

295
00:22:31 --> 00:22:35
And as they do this, a bunch of them also move to the

296
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right hand side of the board. And if you watch, you could see stuff

297
00:22:39 --> 00:22:43
happening. And at the end of the movie,

298
00:22:43 --> 00:22:47
you could see something that might have been somewhat recognizable to

299
00:22:47 --> 00:22:51
you as a developing little animal in that it had an eye,

300
00:22:51 --> 00:22:55
and I'll point this out, and it had a tail. So, let's watch

301
00:22:55 --> 00:23:00
it again and I'll stop it at various points, and I will point out stuff.

302
00:23:00 --> 00:23:03
Where did my mouse go? There it is. OK, so here's the

303
00:23:03 --> 00:23:07
cell division. Cells are dividing. They are dividing,

304
00:23:07 --> 00:23:10
they're dividing, they're dividing, and making this little dome on top

305
00:23:10 --> 00:23:14
of the embryo on top of the yolk. So, this little group of cells is

306
00:23:14 --> 00:23:18
going to give rise to the whole fish. And although humans don't

307
00:23:18 --> 00:23:21
have a yolk cell like this, human embryos look very similar.

308
00:23:21 --> 00:23:25
And now, this group of cells is going to spread out. You will see a

309
00:23:25 --> 00:23:29
kind of haze spreading out over this yolk cell.

310
00:23:29 --> 00:23:33
That's the cells moving. There they go. They're moving,

311
00:23:33 --> 00:23:37
moving, moving, moving, moving down. And at the same time,

312
00:23:37 --> 00:23:42
a bunch of them are moving to the side of the embryo. And as you

313
00:23:42 --> 00:23:46
watch, take a look. Here is the high. This oval is the eye and the

314
00:23:46 --> 00:23:51
brain is going to develop up here. And watch these little shiver and

315
00:23:51 --> 00:23:55
shaky things on the side as well. Those are the developing muscles.

316
00:23:55 --> 00:24:00
OK, and so, there it goes, a lot of shape forming.

317
00:24:00 --> 00:24:04
And we are going to move on from there. OK, so go and take a look at

318
00:24:04 --> 00:24:08
this at your leisure. We are going to talk about some of those

319
00:24:08 --> 00:24:12
processes again. So, let's move on to the next point that

320
00:24:12 --> 00:24:16
we need to deal with, and that is a point that I've called

321
00:24:16 --> 00:24:20
here cell fate requires differential gene expression. But

322
00:24:20 --> 00:24:24
I'm going to state it more simply on the boards, which are

323
00:24:24 --> 00:24:34
now not responsive.

324
00:24:34 --> 00:24:42
OK, here's an easy way to state this. Genes control development.

325
00:24:42 --> 00:24:50
 OK, well, that doesn't sound so

326
00:24:50 --> 00:24:54
surprising. Genes control everything as far as you've been

327
00:24:54 --> 00:24:58
told, but let's talk about that in a bit more detail. And

328
00:24:58 --> 00:25:02
there are three things you should know about this. Firstly,

329
00:25:02 --> 00:25:06
the function of a cell depends on the specific proteins present.

330
00:25:06 --> 00:25:15
So, cell function depends on specific proteins.

331
00:25:15 --> 00:25:21
 Second thing: all cells contain the

332
00:25:21 --> 00:25:27
same genes or the same set of genes --

333
00:25:27 --> 00:25:38
 And the third thing is that only

334
00:25:38 --> 00:25:42
some of those genes are used in each cell type.

335
00:25:42 --> 00:25:50
 And I'm going to use the term

336
00:25:50 --> 00:25:58
expressed, which we've encountered before. Only some genes are

337
00:25:58 --> 00:26:05
expressed in each cell type. And I'm also going to introduce to

338
00:26:05 --> 00:26:11
you a term called fate where the term is similarly used to the

339
00:26:11 --> 00:26:18
English term fate, but not quite, where fate and

340
00:26:18 --> 00:26:25
development refers to the final form and function of a cell.

341
00:26:25 --> 00:26:33
 All right, so let's see what we

342
00:26:33 --> 00:26:37
have. Here's something we've seen before, this kind of tiresome

343
00:26:37 --> 00:26:41
diagram that's useful and that should be really familiar to you,

344
00:26:41 --> 00:26:45
the passage of information from DNA through an RNA intermediate to a

345
00:26:45 --> 00:26:50
protein product. And the formation of the final product

346
00:26:50 --> 00:26:54
from the gene is termed gene expression. Cell types are

347
00:26:54 --> 00:26:58
different because they make different proteins. We've talked

348
00:26:58 --> 00:27:03
about these three cell types previously.

349
00:27:03 --> 00:27:07
Erythrocytes are so because they're making globin,

350
00:27:07 --> 00:27:12
which carries oxygen around the body. Neurons are making proteins,

351
00:27:12 --> 00:27:17
which send out the filaments, and chemicals that allow nerves to

352
00:27:17 --> 00:27:22
communicate with each other and so on. Number 15 on your hand out,

353
00:27:22 --> 00:27:27
the first slide on your handout, you need to know this really,

354
00:27:27 --> 00:27:34
really clearly. This is important.

355
00:27:34 --> 00:27:40
And part of the deal here is something I'm going to write on the

356
00:27:40 --> 00:27:46
board, firstly, that in any process of figuring out

357
00:27:46 --> 00:27:52
what a cell is going to become, there are multiple steps to a final

358
00:27:52 --> 00:27:58
fate. It doesn't just happen at once.

359
00:27:58 --> 00:28:05
And secondly, I want to make the distinction between regulatory genes

360
00:28:05 --> 00:28:17
and differentiation genes --

361
00:28:17 --> 00:28:24
-- where regulatory genes, we can rephrase this, control cell

362
00:28:24 --> 00:28:32
fate, and differentiation genes affect cell fate.

363
00:28:32 --> 00:28:37
They carry out cell fate. And here is a litany that I've written

364
00:28:37 --> 00:28:42
out for you that is important that you know. In the life of a cell,

365
00:28:42 --> 00:28:47
as it's deciding what to become, it goes through multiple stages. It

366
00:28:47 --> 00:28:52
starts off not knowing what it's going to become,

367
00:28:52 --> 00:28:58
and we call those uncommitted cells. Kind of like you when you came to

368
00:28:58 --> 00:29:03
MIT, you were uncommitted and perhaps still are as to what you're

369
00:29:03 --> 00:29:08
going to do next. But over time,

370
00:29:08 --> 00:29:12
through the passage of time, you get various inputs and you

371
00:29:12 --> 00:29:16
decide what you are going to become either as a cell or as an MIT

372
00:29:16 --> 00:29:20
student. And at that point, you are called committed or

373
00:29:20 --> 00:29:24
determined. That's the jargon. You need to know it. It's very

374
00:29:24 --> 00:29:28
important. Committed or determined cells have made the decision what to

375
00:29:28 --> 00:29:32
be. But they haven't gone on and become the final thing that

376
00:29:32 --> 00:29:36
they're going to be. So, maybe you are premed,

377
00:29:36 --> 00:29:40
and by now you have committed to being premed. So,

378
00:29:40 --> 00:29:44
you are different than when you came in here, but you certainly are not a

379
00:29:44 --> 00:29:48
qualified physician at this point. In order to do that,

380
00:29:48 --> 00:29:51
you're going to have to go through another bunch of steps and find your

381
00:29:51 --> 00:29:55
final form. You're going to have to differentiate into a physician or

382
00:29:55 --> 00:29:59
into a cell type. So, this uncommitted-committed

383
00:29:59 --> 00:30:03
differentiated litany triad is something we're going to talk

384
00:30:03 --> 00:30:07
about over and over. It's going to come up throughout the

385
00:30:07 --> 00:30:11
course probably in most of the lectures that both I and Professor

386
00:30:11 --> 00:30:16
Jacks will give you. During this passage, and you've got the slide,

387
00:30:16 --> 00:30:20
this is the slide you actually have, is two sets of genes are activated,

388
00:30:20 --> 00:30:25
regulatory genes and differentiation genes. As the uncommitted cells

389
00:30:25 --> 00:30:30
decide what they're going to be, regulatory genes are activated.

390
00:30:30 --> 00:30:34
As the committed cells go on to read out the final thing,

391
00:30:34 --> 00:30:38
their final function, the activation of differentiation

392
00:30:38 --> 00:30:42
genes takes place. So, how does it work? How does a cell

393
00:30:42 --> 00:30:46
decide what to become, and how do different cells decide to

394
00:30:46 --> 00:30:50
become different things? Well, this is the way I think about

395
00:30:50 --> 00:30:54
this. This isn't the way your book thinks about it,

396
00:30:54 --> 00:30:58
but this is the way I think about it. I think that there is a

397
00:30:58 --> 00:31:03
combinatorial regulatory code that controls cell type.

398
00:31:03 --> 00:31:07
And so, let's have an example of the three cell types I've talked about

399
00:31:07 --> 00:31:11
before, your erythrocyte neuron and sperm. And let's look at the

400
00:31:11 --> 00:31:16
regulatory genes that each expresses. You can look on the

401
00:31:16 --> 00:31:20
screen. You have this in front of you as a handout. So,

402
00:31:20 --> 00:31:25
I've arbitrarily said that an erythrocyte is expressing regulatory

403
00:31:25 --> 00:31:29
genes, R, F, and K, the neurons expressing A,

404
00:31:29 --> 00:31:34
I, and K, and the sperm is expressing A, F, and K.

405
00:31:34 --> 00:31:39
OK, now let's look at those. Those three groups of three letters are

406
00:31:39 --> 00:31:44
different from one another. And so, for each of these cell types, there

407
00:31:44 --> 00:31:49
is a unique set of letters or a unique regulatory code. What's this

408
00:31:49 --> 00:31:55
code made up of? Well, it's made up of cell type

409
00:31:55 --> 00:32:00
specific factors, or cell type specific regulatory

410
00:32:00 --> 00:32:05
genes, regulatory gene products. RNI are expressed in just the

411
00:32:05 --> 00:32:10
erythrocyte, or just the neuron. They are cell type specific

412
00:32:10 --> 00:32:15
regulators. General factors, K is expressed in all of the cells,

413
00:32:15 --> 00:32:20
and restricted factors, F and A, are expressed in just two of the three

414
00:32:20 --> 00:32:25
cells. And you can do that for any cell type. You can come up with

415
00:32:25 --> 00:32:30
some kind of combinatorial code of gene expression of regulatory genes

416
00:32:30 --> 00:32:35
that control cell fate. Now, these regulatory genes will go

417
00:32:35 --> 00:32:39
on to activate the expression of a whole bunch of differentiation

418
00:32:39 --> 00:32:43
genes. And usually a small set of regulatory genes will activate a

419
00:32:43 --> 00:32:47
large set of differentiation genes that carry out the final function.

420
00:32:47 --> 00:32:51
So, here I've given you an example for erythrocytes. It's,

421
00:32:51 --> 00:32:56
again, on your handouts. The regulatory code for erythrocytes,

422
00:32:56 --> 00:33:00
RFK, a small regulatory code, actually it's probably about 20

423
00:33:00 --> 00:33:04
genes, will go on and activate at least a hundred genes which will be

424
00:33:04 --> 00:33:08
the gene products that actually carry out the function

425
00:33:08 --> 00:33:14
of red blood cells. OK, so regulatory genes activate

426
00:33:14 --> 00:33:20
differentiation genes. What's all this regulatory stuff?

427
00:33:20 --> 00:33:26
What are these regulatory genes? So, here you have to think back to

428
00:33:26 --> 00:33:32
previous lectures. Remember this diagram? You have it.

429
00:33:32 --> 00:33:36
You've had it several times. This is the hierarchy of things that

430
00:33:36 --> 00:33:40
happened from the gene in the nucleus to the final,

431
00:33:40 --> 00:33:44
modified, localized protein products. You can control,

432
00:33:44 --> 00:33:48
the cell can control gene expression at any point along this hierarchy.

433
00:33:48 --> 00:33:52
It can control transcription, initiation, or termination, RNA

434
00:33:52 --> 00:33:56
splicing, stability or exports, translation, the initiation or

435
00:33:56 --> 00:34:00
elongation. It can control export of proteins to different parts of

436
00:34:00 --> 00:34:04
the cell through protein trafficking, modification and control

437
00:34:04 --> 00:34:09
of protein stability. And there are more. OK,

438
00:34:09 --> 00:34:14
this is some of the list of steps at which gene expression can be

439
00:34:14 --> 00:34:19
regulated. And those hypothetical regulatory

440
00:34:19 --> 00:34:24
factors I told you about in the last couple of slides can be anything

441
00:34:24 --> 00:34:29
that affect any of these steps from the gene to the final product. OK,

442
00:34:29 --> 00:34:34
all right, so here's another one that you need to know.

443
00:34:34 --> 00:34:37
Complexity increases with developmental age.

444
00:34:37 --> 00:34:57
 And what I'm going to tell you

445
00:34:57 --> 00:35:03
about is how as development proceeds, as you get different cell types

446
00:35:03 --> 00:35:09
forming, you have to make groups of cells with specific

447
00:35:09 --> 00:35:25
regulatory codes.

448
00:35:25 --> 00:35:37
And these cells --

449
00:35:37 --> 00:35:40
And these regulatory codes will lead to a specific fate. So,

450
00:35:40 --> 00:35:44
here's a nice example just by looking at development of an organ,

451
00:35:44 --> 00:35:48
for example, and this is important if you're going to try to engineer

452
00:35:48 --> 00:35:52
an organ through tissue engineering. You have to understand there are

453
00:35:52 --> 00:35:56
normally many, many steps involved. These are the

454
00:35:56 --> 00:36:00
beginning steps in formation of the eye.

455
00:36:00 --> 00:36:04
And it doesn't matter what each of these steps are,

456
00:36:04 --> 00:36:08
but if you look at the progression of cells, each of these lines are

457
00:36:08 --> 00:36:12
groups of cells. You can see that they organized in different ways.

458
00:36:12 --> 00:36:16
They fold. Bits break off, and you'll end up with a structure

459
00:36:16 --> 00:36:20
that's a lot more complex just in a pictorial way than it was in the

460
00:36:20 --> 00:36:24
beginning. And that is true in terms of every aspect of this organ.

461
00:36:24 --> 00:36:28
It is more complex at the end than at the beginning. And

462
00:36:28 --> 00:36:32
somewhere through here, you have to increase the complexity of

463
00:36:32 --> 00:36:36
this developing tissue. So, how do you do it?

464
00:36:36 --> 00:36:41
This is the way I like to think about this, and this is number 20 of

465
00:36:41 --> 00:36:46
your handout. Here's an egg or a zygote, if you like,

466
00:36:46 --> 00:36:50
a one cell embryo. It's one cell. There's only one kind of cell there.

467
00:36:50 --> 00:36:55
Or, I like to think in terms of territories. There's only one

468
00:36:55 --> 00:37:00
territory there. Now, I've also put a red dot in the

469
00:37:00 --> 00:37:05
cell. And this red dot can be anything.

470
00:37:05 --> 00:37:09
But it really is in terms of our conversation a group of regulatory

471
00:37:09 --> 00:37:14
gene products, or one regulatory gene product.

472
00:37:14 --> 00:37:18
Watch what happens when in my hypothetical example the cell

473
00:37:18 --> 00:37:22
divides. The red dot goes to one cell, and not the other cell. And

474
00:37:22 --> 00:37:27
so, now I've got two different kinds of cells. The regulators are in one

475
00:37:27 --> 00:37:31
cell and not in the other cell. And then, I've gone through

476
00:37:31 --> 00:37:36
this and done it again. When the cells go to four cells,

477
00:37:36 --> 00:37:40
suddenly I've magically put a blue dot in one of the cells,

478
00:37:40 --> 00:37:44
and there's a red dot in another cell, and there's some cells with no

479
00:37:44 --> 00:37:49
dots. And those give me three different kinds of cells,

480
00:37:49 --> 00:37:53
or if you like, three different kinds of territories. And

481
00:37:53 --> 00:37:57
for territories, you can read regulatory code, set of regulatory

482
00:37:57 --> 00:38:02
gene products. So, what have we done?

483
00:38:02 --> 00:38:06
What we have done in this example is to take a zygote or an egg,

484
00:38:06 --> 00:38:10
if you like, that is symmetric at least along one axis,

485
00:38:10 --> 00:38:14
and to divide it so that it's now got two daughters cells that are

486
00:38:14 --> 00:38:18
different from one another. So, there is a breaking of symmetry

487
00:38:18 --> 00:38:22
somewhere in this process. Now, in actual fact, if you look at the

488
00:38:22 --> 00:38:26
egg, it's really only symmetric in one axis. And so, it's not

489
00:38:26 --> 00:38:31
uniformly symmetric. But one of the things we think

490
00:38:31 --> 00:38:36
about in development is that every time you make a new cell type,

491
00:38:36 --> 00:38:41
you have to break symmetry. You get two different kinds of cell from one

492
00:38:41 --> 00:38:51
kind of cell. All right --

493
00:38:51 --> 00:38:55
So, I'll come back to that diagram in a moment, but I want to,

494
00:38:55 --> 00:39:00
the fifth point I want to give you is that regulatory factors act

495
00:39:00 --> 00:39:19
within cells and between cells.

496
00:39:19 --> 00:39:25
Really important, that's why it's up on the screen and

497
00:39:25 --> 00:39:32
it's on the board. I'm going to tell you about three things. I'm

498
00:39:32 --> 00:39:38
going to tell you about regulatory factors that are given the term,

499
00:39:38 --> 00:39:45
determinants that work in a cell autonomous way. That means with

500
00:39:45 --> 00:39:51
inside the cell that carries them. I want to tell you about regulators

501
00:39:51 --> 00:39:58
called inducers that act between cells or in cell-cell signaling.

502
00:39:58 --> 00:40:04
And I'm going to tell you about a subset of inducers called morphogens,

503
00:40:04 --> 00:40:10
which work in a concentration dependent way.

504
00:40:10 --> 00:40:22
 So, this is a kind of magic,

505
00:40:22 --> 00:40:28
and it isn't a kind of magic. The molecules I'll tell you about our

506
00:40:28 --> 00:40:34
molecules that you've heard about previously, OK?

507
00:40:34 --> 00:40:40
 The phrasing, the jargon is a little

508
00:40:40 --> 00:40:44
different and you need to learn it because this is jargon that's used

509
00:40:44 --> 00:40:48
throughout biology. Let's first of all talk about these things called

510
00:40:48 --> 00:40:52
determinants. And the notion here is that cells become

511
00:40:52 --> 00:40:57
different because of what they inherit. And

512
00:40:57 --> 00:41:01
I've drawn for you here, and this is number 21 on your

513
00:41:01 --> 00:41:05
handout, I've drawn for you here a cell, this blue thing

514
00:41:05 --> 00:41:10
with squares in it. The squares are determinants,

515
00:41:10 --> 00:41:14
and determinants are some kind of regulatory factor. They may be one

516
00:41:14 --> 00:41:18
regulatory factor, maybe more than one regulatory

517
00:41:18 --> 00:41:23
factor. They may be transcription factors. They may be splicing

518
00:41:23 --> 00:41:27
factors. They may be micro-RNA's. They may be all the things we've

519
00:41:27 --> 00:41:32
talked about in previous lectures, but I've drawn them as squares.

520
00:41:32 --> 00:41:35
And here's a cell with those little squares. And I've drawn it so that

521
00:41:35 --> 00:41:39
all the squares are on one side and not the other. And

522
00:41:39 --> 00:41:43
of course, you're sitting there asking, how did the squares get on

523
00:41:43 --> 00:41:47
one side but not the other? And that is a really good

524
00:41:47 --> 00:41:51
question. And I'm not going to tell you how to get

525
00:41:51 --> 00:41:55
on one side but not the other. But there is a whole system in the cell

526
00:41:55 --> 00:41:59
of pulleys using things like microtubules where specific squares,

527
00:41:59 --> 00:42:03
specific molecules, can actually be pulled to one side of the

528
00:42:03 --> 00:42:06
cell or the other. And then, you're going to ask me,

529
00:42:06 --> 00:42:10
well, how do they know which side of the cell to move to?

530
00:42:10 --> 00:42:13
And that's another great question that I'm not going to answer. But

531
00:42:13 --> 00:42:16
suffice to say there is a whole molecular machinery that can move

532
00:42:16 --> 00:42:20
regulatory molecules to different places in the cell. But

533
00:42:20 --> 00:42:23
let's go back to our cell that's got squares on one side and not on the

534
00:42:23 --> 00:42:27
other. When it divides, it gives rise to a cell that's got

535
00:42:27 --> 00:42:30
lots of squares, lots of determinants,

536
00:42:30 --> 00:42:34
and another cell that doesn't have any.

537
00:42:34 --> 00:42:38
The cell with the determinants goes on to make cell type one because it

538
00:42:38 --> 00:42:42
has a specific set of regulatory factors. The cell without them goes

539
00:42:42 --> 00:42:46
on to make another cell type. It's not that it doesn't have any

540
00:42:46 --> 00:42:50
regulators; it just doesn't have the ones in the squares. So,

541
00:42:50 --> 00:42:54
cells are different because of what they inherit. Here is a fantastic

542
00:42:54 --> 00:42:58
example. These are early worm embryos, early embryos

543
00:42:58 --> 00:43:02
of [scientific name]. We mentioned this last time that

544
00:43:02 --> 00:43:06
Professor Horvitz in the biology department got the

545
00:43:06 --> 00:43:10
Nobel Prize for it several years ago. And this is an example of

546
00:43:10 --> 00:43:14
determinants moving to different cells during development. So,

547
00:43:14 --> 00:43:19
the top row are cells that have been stained for their nuclei. And

548
00:43:19 --> 00:43:23
you can see one cell, two cell, and 32 cell stage embryo. These bottom

549
00:43:23 --> 00:43:27
pictures are florescent pictures of things called pea granules. These

550
00:43:27 --> 00:43:32
are determinants. And you can see even at the one cell

551
00:43:32 --> 00:43:36
stage, there are all located on one side of the cell. At the two cell

552
00:43:36 --> 00:43:41
stage, they all go to one of the two cells. And at the 32 cell stage,

553
00:43:41 --> 00:43:45
they are all in the cell over here. And those cells or that cell is

554
00:43:45 --> 00:43:50
going to give rise to the egg and sperm of [scientific name]

555
00:43:50 --> 00:43:55
, and those pea granules are determinants for the germ cells.

556
00:43:55 --> 00:43:59
Here's the other big thing. Cell-cell signaling: cells

557
00:43:59 --> 00:44:04
may secrete an inducer. This is a ligand. Remember signal

558
00:44:04 --> 00:44:08
transduction that you talked about in cell biology II?

559
00:44:08 --> 00:44:13
Those same ligands that are secreted by cells bind to receptors

560
00:44:13 --> 00:44:18
on target cells. Receptor ligand interaction leads to activation of

561
00:44:18 --> 00:44:22
signal transduction pathways, again, from cell biology II. And

562
00:44:22 --> 00:44:27
that over time can change the genes that a cell is expressing and

563
00:44:27 --> 00:44:32
changed the fate of the cell. So, we call these things inducers

564
00:44:32 --> 00:44:36
because of the specific assays involved. But really,

565
00:44:36 --> 00:44:40
they're ligands, often proteins, sometimes lipids, that bind

566
00:44:40 --> 00:44:44
receptors, activate signal transduction, and change cell fate.

567
00:44:44 --> 00:44:48
This is number 23 on your handout. So, induction: a process by which

568
00:44:48 --> 00:44:52
cells become different because their neighbors tell them to do so,

569
00:44:52 --> 00:44:56
and a variation of induction, oh, here's an example of induction, sea

570
00:44:56 --> 00:45:00
urchin embryo, the induction is everywhere.

571
00:45:00 --> 00:45:04
But I've picked this one example. Sea urchin embryo goes on through

572
00:45:04 --> 00:45:08
time to make this little thing called a pluteus larva. If you

573
00:45:08 --> 00:45:12
remove the bottom half of the embryo, it goes on. The rest goes on to

574
00:45:12 --> 00:45:17
make a kind of a round thing with lots of cilia sticking out. And

575
00:45:17 --> 00:45:21
you can take four little cells that were right on the bottom of the

576
00:45:21 --> 00:45:25
normal embryo called micro-mirrors and stick them back on this top half

577
00:45:25 --> 00:45:30
of the embryo that didn't make a normal one.

578
00:45:30 --> 00:45:34
And it will restore a pretty normal embryo. And it's not that the red

579
00:45:34 --> 00:45:38
cells have made all the parts of the embryo that we're missing,

580
00:45:38 --> 00:45:42
or the parts of the larva that were missing. It's that those red cells

581
00:45:42 --> 00:45:46
have sent out a signal, and that signal has told other cells

582
00:45:46 --> 00:45:50
what to become. And in the case of the sea urchin,

583
00:45:50 --> 00:45:54
part of that signal is something called the delta protein. This is a

584
00:45:54 --> 00:45:58
micrograph of the a sea urchin embryo at a very early stage,

585
00:45:58 --> 00:46:02
and this brown-purple group of cells here are those cells that contain

586
00:46:02 --> 00:46:06
the delta protein. These are the micro-mirrors,

587
00:46:06 --> 00:46:10
and these are involved in inducing the rest of the embryo to become

588
00:46:10 --> 00:46:14
what it does. Now, inducers, ligands, can be tricky.

589
00:46:14 --> 00:46:18
They can act in different ways at different concentrations. And

590
00:46:18 --> 00:46:23
this is one of the big questions of biology. How do they do this?

591
00:46:23 --> 00:46:27
So, for example, if you have a lot of an inducer,

592
00:46:27 --> 00:46:31
it may tell cells to become cell type one. If you have a little bit

593
00:46:31 --> 00:46:35
of an inducer, it may tell cells to become cell

594
00:46:35 --> 00:46:40
type two. And we'll talk about in a

595
00:46:40 --> 00:46:44
subsequent lecture the molecular basis for this. So,

596
00:46:44 --> 00:46:49
an inducer that can induce different fates at different concentrations is

597
00:46:49 --> 46:52
terms a morphogen --