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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,

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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

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

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

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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

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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,

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I have 10,000 fish. If you want to come and visit my laboratory and see

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

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And I'm going to use this movie and this embryo to show you something

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about the sequence of events that take place during development. I

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want you to look for cell division, and I want you to look for

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structural changes as you watch the movie. Let's look at the movie

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again without the music. And let me show you what you're looking at. So,

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to zebra fish, like the chicken,

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and actually almost like the human develops as a disk of cells,

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or from a little disk of cells. I'll show this to you again when it

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starts again, that sits on top of a yolk cell. Chickens have got a yolk

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cell. That's the yolk of egg. Humans don't. But otherwise things

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are very similar. Let me try to start that. OK,

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good. So, we're going to look at this again. Here is the yolk cell.

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This big round ball here is the so-called yolk cell,

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and that's going to be the food of the embryo. These two bumps

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on top are two cells. This is a two cell stage embryo.

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And as you watch the movie for the last time, and I'll post it on your

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website so you can watch it as much as you want, you'll see these two

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cells divide into four cells, and eight cells, and 16 cells,

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and so on, until they've made a little dome of cells sitting on top

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of the yolk cell. And then, at that point, suddenly at some

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point, and this is very interesting. That group of cells realizes that

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there's enough of them, and they start to move. And they

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spread out to cover the whole yolk cell.

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And as they do this, a bunch of them also move to the

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

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happening. And at the end of the movie,

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you could see something that might have been somewhat recognizable to

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you as a developing little animal in that it had an eye,

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and I'll point this out, and it had a tail. So, let's watch

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it again and I'll stop it at various points, and I will point out stuff.

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Where did my mouse go? There it is. OK, so here's the

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cell division. Cells are dividing. They are dividing,

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they're dividing, they're dividing, and making this little dome on top

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of the embryo on top of the yolk. So, this little group of cells is

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going to give rise to the whole fish. And although humans don't

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have a yolk cell like this, human embryos look very similar.

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And now, this group of cells is going to spread out. You will see a

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kind of haze spreading out over this yolk cell.

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That's the cells moving. There they go. They're moving,

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moving, moving, moving, moving down. And at the same time,

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a bunch of them are moving to the side of the embryo. And as you

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watch, take a look. Here is the high. This oval is the eye and the

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brain is going to develop up here. And watch these little shiver and

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shaky things on the side as well. Those are the developing muscles.

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OK, and so, there it goes, a lot of shape forming.

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And we are going to move on from there. OK, so go and take a look at

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this at your leisure. We are going to talk about some of those

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00:24:08,000 --> 00:24:12,000
processes again. So, let's move on to the next point that

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we need to deal with, and that is a point that I've called

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here cell fate requires differential gene expression. But

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I'm going to state it more simply on the boards, which are

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now not responsive.

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OK, here's an easy way to state this. Genes control development.

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OK, well, that doesn't sound so

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surprising. Genes control everything as far as you've been

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told, but let's talk about that in a bit more detail. And

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there are three things you should know about this. Firstly,

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the function of a cell depends on the specific proteins present.

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So, cell function depends on specific proteins.

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Second thing: all cells contain the

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same genes or the same set of genes --

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And the third thing is that only

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some of those genes are used in each cell type.

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And I'm going to use the term

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expressed, which we've encountered before. Only some genes are

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expressed in each cell type. And I'm also going to introduce to

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you a term called fate where the term is similarly used to the

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00:26:11,000 --> 00:26:18,000
English term fate, but not quite, where fate and

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development refers to the final form and function of a cell.

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All right, so let's see what we

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have. Here's something we've seen before, this kind of tiresome

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00:26:37,000 --> 00:26:41,000
diagram that's useful and that should be really familiar to you,

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the passage of information from DNA through an RNA intermediate to a

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protein product. And the formation of the final product

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from the gene is termed gene expression. Cell types are

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different because they make different proteins. We've talked

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about these three cell types previously.

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Erythrocytes are so because they're making globin,

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which carries oxygen around the body. Neurons are making proteins,

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which send out the filaments, and chemicals that allow nerves to

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communicate with each other and so on. Number 15 on your hand out,

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00:27:22,000 --> 00:27:27,000
the first slide on your handout, you need to know this really,

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really clearly. This is important.

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And part of the deal here is something I'm going to write on the

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board, firstly, that in any process of figuring out

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what a cell is going to become, there are multiple steps to a final

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fate. It doesn't just happen at once.

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And secondly, I want to make the distinction between regulatory genes

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and differentiation genes --

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-- where regulatory genes, we can rephrase this, control cell

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fate, and differentiation genes affect cell fate.

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They carry out cell fate. And here is a litany that I've written

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00:28:37,000 --> 00:28:42,000
out for you that is important that you know. In the life of a cell,

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00:28:42,000 --> 00:28:47,000
as it's deciding what to become, it goes through multiple stages. It

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starts off not knowing what it's going to become,

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and we call those uncommitted cells. Kind of like you when you came to

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MIT, you were uncommitted and perhaps still are as to what you're

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going to do next. But over time,

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00:29:08,000 --> 00:29:12,000
through the passage of time, you get various inputs and you

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00:29:12,000 --> 00:29:16,000
decide what you are going to become either as a cell or as an MIT

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00:29:16,000 --> 00:29:20,000
student. And at that point, you are called committed or

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determined. That's the jargon. You need to know it. It's very

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00:29:24,000 --> 00:29:28,000
important. Committed or determined cells have made the decision what to

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00:29:28,000 --> 00:29:32,000
be. But they haven't gone on and become the final thing that

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00:29:32,000 --> 00:29:36,000
they're going to be. So, maybe you are premed,

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00:29:36,000 --> 00:29:40,000
and by now you have committed to being premed. So,

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00:29:40,000 --> 00:29:44,000
you are different than when you came in here, but you certainly are not a

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00:29:44,000 --> 00:29:48,000
qualified physician at this point. In order to do that,

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00:29:48,000 --> 00:29:51,000
you're going to have to go through another bunch of steps and find your

381
00:29:51,000 --> 00:29:55,000
final form. You're going to have to differentiate into a physician or

382
00:29:55,000 --> 00:29:59,000
into a cell type. So, this uncommitted-committed

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00:29:59,000 --> 00:30:03,000
differentiated litany triad is something we're going to talk

384
00:30:03,000 --> 00:30:07,000
about over and over. It's going to come up throughout the

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00:30:07,000 --> 00:30:11,000
course probably in most of the lectures that both I and Professor

386
00:30:11,000 --> 00:30:16,000
Jacks will give you. During this passage, and you've got the slide,

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00:30:16,000 --> 00:30:20,000
this is the slide you actually have, is two sets of genes are activated,

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00:30:20,000 --> 00:30:25,000
regulatory genes and differentiation genes. As the uncommitted cells

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00:30:25,000 --> 00:30:30,000
decide what they're going to be, regulatory genes are activated.

390
00:30:30,000 --> 00:30:34,000
As the committed cells go on to read out the final thing,

391
00:30:34,000 --> 00:30:38,000
their final function, the activation of differentiation

392
00:30:38,000 --> 00:30:42,000
genes takes place. So, how does it work? How does a cell

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00:30:42,000 --> 00:30:46,000
decide what to become, and how do different cells decide to

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00:30:46,000 --> 00:30:50,000
become different things? Well, this is the way I think about

395
00:30:50,000 --> 00:30:54,000
this. This isn't the way your book thinks about it,

396
00:30:54,000 --> 00:30:58,000
but this is the way I think about it. I think that there is a

397
00:30:58,000 --> 00:31:03,000
combinatorial regulatory code that controls cell type.

398
00:31:03,000 --> 00:31:07,000
And so, let's have an example of the three cell types I've talked about

399
00:31:07,000 --> 00:31:11,000
before, your erythrocyte neuron and sperm. And let's look at the

400
00:31:11,000 --> 00:31:16,000
regulatory genes that each expresses. You can look on the

401
00:31:16,000 --> 00:31:20,000
screen. You have this in front of you as a handout. So,

402
00:31:20,000 --> 00:31:25,000
I've arbitrarily said that an erythrocyte is expressing regulatory

403
00:31:25,000 --> 00:31:29,000
genes, R, F, and K, the neurons expressing A,

404
00:31:29,000 --> 00:31:34,000
I, and K, and the sperm is expressing A, F, and K.

405
00:31:34,000 --> 00:31:39,000
OK, now let's look at those. Those three groups of three letters are

406
00:31:39,000 --> 00:31:44,000
different from one another. And so, for each of these cell types, there

407
00:31:44,000 --> 00:31:49,000
is a unique set of letters or a unique regulatory code. What's this

408
00:31:49,000 --> 00:31:55,000
code made up of? Well, it's made up of cell type

409
00:31:55,000 --> 00:32:00,000
specific factors, or cell type specific regulatory

410
00:32:00,000 --> 00:32:05,000
genes, regulatory gene products. RNI are expressed in just the

411
00:32:05,000 --> 00:32:10,000
erythrocyte, or just the neuron. They are cell type specific

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00:32:10,000 --> 00:32:15,000
regulators. General factors, K is expressed in all of the cells,

413
00:32:15,000 --> 00:32:20,000
and restricted factors, F and A, are expressed in just two of the three

414
00:32:20,000 --> 00:32:25,000
cells. And you can do that for any cell type. You can come up with

415
00:32:25,000 --> 00:32:30,000
some kind of combinatorial code of gene expression of regulatory genes

416
00:32:30,000 --> 00:32:35,000
that control cell fate. Now, these regulatory genes will go

417
00:32:35,000 --> 00:32:39,000
on to activate the expression of a whole bunch of differentiation

418
00:32:39,000 --> 00:32:43,000
genes. And usually a small set of regulatory genes will activate a

419
00:32:43,000 --> 00:32:47,000
large set of differentiation genes that carry out the final function.

420
00:32:47,000 --> 00:32:51,000
So, here I've given you an example for erythrocytes. It's,

421
00:32:51,000 --> 00:32:56,000
again, on your handouts. The regulatory code for erythrocytes,

422
00:32:56,000 --> 00:33:00,000
RFK, a small regulatory code, actually it's probably about 20

423
00:33:00,000 --> 00:33:04,000
genes, will go on and activate at least a hundred genes which will be

424
00:33:04,000 --> 00:33:08,000
the gene products that actually carry out the function

425
00:33:08,000 --> 00:33:14,000
of red blood cells. OK, so regulatory genes activate

426
00:33:14,000 --> 00:33:20,000
differentiation genes. What's all this regulatory stuff?

427
00:33:20,000 --> 00:33:26,000
What are these regulatory genes? So, here you have to think back to

428
00:33:26,000 --> 00:33:32,000
previous lectures. Remember this diagram? You have it.

429
00:33:32,000 --> 00:33:36,000
You've had it several times. This is the hierarchy of things that

430
00:33:36,000 --> 00:33:40,000
happened from the gene in the nucleus to the final,

431
00:33:40,000 --> 00:33:44,000
modified, localized protein products. You can control,

432
00:33:44,000 --> 00:33:48,000
the cell can control gene expression at any point along this hierarchy.

433
00:33:48,000 --> 00:33:52,000
It can control transcription, initiation, or termination, RNA

434
00:33:52,000 --> 00:33:56,000
splicing, stability or exports, translation, the initiation or

435
00:33:56,000 --> 00:34:00,000
elongation. It can control export of proteins to different parts of

436
00:34:00,000 --> 00:34:04,000
the cell through protein trafficking, modification and control

437
00:34:04,000 --> 00:34:09,000
of protein stability. And there are more. OK,

438
00:34:09,000 --> 00:34:14,000
this is some of the list of steps at which gene expression can be

439
00:34:14,000 --> 00:34:19,000
regulated. And those hypothetical regulatory

440
00:34:19,000 --> 00:34:24,000
factors I told you about in the last couple of slides can be anything

441
00:34:24,000 --> 00:34:29,000
that affect any of these steps from the gene to the final product. OK,

442
00:34:29,000 --> 00:34:34,000
all right, so here's another one that you need to know.

443
00:34:34,000 --> 00:34:37,000
Complexity increases with developmental age.

444
00:34:37,000 --> 00:34:57,000
And what I'm going to tell you

445
00:34:57,000 --> 00:35:03,000
about is how as development proceeds, as you get different cell types

446
00:35:03,000 --> 00:35:09,000
forming, you have to make groups of cells with specific

447
00:35:09,000 --> 00:35:25,000
regulatory codes.

448
00:35:25,000 --> 00:35:37,000
And these cells --

449
00:35:37,000 --> 00:35:40,000
And these regulatory codes will lead to a specific fate. So,

450
00:35:40,000 --> 00:35:44,000
here's a nice example just by looking at development of an organ,

451
00:35:44,000 --> 00:35:48,000
for example, and this is important if you're going to try to engineer

452
00:35:48,000 --> 00:35:52,000
an organ through tissue engineering. You have to understand there are

453
00:35:52,000 --> 00:35:56,000
normally many, many steps involved. These are the

454
00:35:56,000 --> 00:36:00,000
beginning steps in formation of the eye.

455
00:36:00,000 --> 00:36:04,000
And it doesn't matter what each of these steps are,

456
00:36:04,000 --> 00:36:08,000
but if you look at the progression of cells, each of these lines are

457
00:36:08,000 --> 00:36:12,000
groups of cells. You can see that they organized in different ways.

458
00:36:12,000 --> 00:36:16,000
They fold. Bits break off, and you'll end up with a structure

459
00:36:16,000 --> 00:36:20,000
that's a lot more complex just in a pictorial way than it was in the

460
00:36:20,000 --> 00:36:24,000
beginning. And that is true in terms of every aspect of this organ.

461
00:36:24,000 --> 00:36:28,000
It is more complex at the end than at the beginning. And

462
00:36:28,000 --> 00:36:32,000
somewhere through here, you have to increase the complexity of

463
00:36:32,000 --> 00:36:36,000
this developing tissue. So, how do you do it?

464
00:36:36,000 --> 00:36:41,000
This is the way I like to think about this, and this is number 20 of

465
00:36:41,000 --> 00:36:46,000
your handout. Here's an egg or a zygote, if you like,

466
00:36:46,000 --> 00:36:50,000
a one cell embryo. It's one cell. There's only one kind of cell there.

467
00:36:50,000 --> 00:36:55,000
Or, I like to think in terms of territories. There's only one

468
00:36:55,000 --> 00:37:00,000
territory there. Now, I've also put a red dot in the

469
00:37:00,000 --> 00:37:05,000
cell. And this red dot can be anything.

470
00:37:05,000 --> 00:37:09,000
But it really is in terms of our conversation a group of regulatory

471
00:37:09,000 --> 00:37:14,000
gene products, or one regulatory gene product.

472
00:37:14,000 --> 00:37:18,000
Watch what happens when in my hypothetical example the cell

473
00:37:18,000 --> 00:37:22,000
divides. The red dot goes to one cell, and not the other cell. And

474
00:37:22,000 --> 00:37:27,000
so, now I've got two different kinds of cells. The regulators are in one

475
00:37:27,000 --> 00:37:31,000
cell and not in the other cell. And then, I've gone through

476
00:37:31,000 --> 00:37:36,000
this and done it again. When the cells go to four cells,

477
00:37:36,000 --> 00:37:40,000
suddenly I've magically put a blue dot in one of the cells,

478
00:37:40,000 --> 00:37:44,000
and there's a red dot in another cell, and there's some cells with no

479
00:37:44,000 --> 00:37:49,000
dots. And those give me three different kinds of cells,

480
00:37:49,000 --> 00:37:53,000
or if you like, three different kinds of territories. And

481
00:37:53,000 --> 00:37:57,000
for territories, you can read regulatory code, set of regulatory

482
00:37:57,000 --> 00:38:02,000
gene products. So, what have we done?

483
00:38:02,000 --> 00:38:06,000
What we have done in this example is to take a zygote or an egg,

484
00:38:06,000 --> 00:38:10,000
if you like, that is symmetric at least along one axis,

485
00:38:10,000 --> 00:38:14,000
and to divide it so that it's now got two daughters cells that are

486
00:38:14,000 --> 00:38:18,000
different from one another. So, there is a breaking of symmetry

487
00:38:18,000 --> 00:38:22,000
somewhere in this process. Now, in actual fact, if you look at the

488
00:38:22,000 --> 00:38:26,000
egg, it's really only symmetric in one axis. And so, it's not

489
00:38:26,000 --> 00:38:31,000
uniformly symmetric. But one of the things we think

490
00:38:31,000 --> 00:38:36,000
about in development is that every time you make a new cell type,

491
00:38:36,000 --> 00:38:41,000
you have to break symmetry. You get two different kinds of cell from one

492
00:38:41,000 --> 00:38:51,000
kind of cell. All right --

493
00:38:51,000 --> 00:38:55,000
So, I'll come back to that diagram in a moment, but I want to,

494
00:38:55,000 --> 00:39:00,000
the fifth point I want to give you is that regulatory factors act

495
00:39:00,000 --> 00:39:19,000
within cells and between cells.

496
00:39:19,000 --> 00:39:25,000
Really important, that's why it's up on the screen and

497
00:39:25,000 --> 00:39:32,000
it's on the board. I'm going to tell you about three things. I'm

498
00:39:32,000 --> 00:39:38,000
going to tell you about regulatory factors that are given the term,

499
00:39:38,000 --> 00:39:45,000
determinants that work in a cell autonomous way. That means with

500
00:39:45,000 --> 00:39:51,000
inside the cell that carries them. I want to tell you about regulators

501
00:39:51,000 --> 00:39:58,000
called inducers that act between cells or in cell-cell signaling.

502
00:39:58,000 --> 00:40:04,000
And I'm going to tell you about a subset of inducers called morphogens,

503
00:40:04,000 --> 00:40:10,000
which work in a concentration dependent way.

504
00:40:10,000 --> 00:40:22,000
So, this is a kind of magic,

505
00:40:22,000 --> 00:40:28,000
and it isn't a kind of magic. The molecules I'll tell you about our

506
00:40:28,000 --> 00:40:34,000
molecules that you've heard about previously, OK?

507
00:40:34,000 --> 00:40:40,000
The phrasing, the jargon is a little

508
00:40:40,000 --> 00:40:44,000
different and you need to learn it because this is jargon that's used

509
00:40:44,000 --> 00:40:48,000
throughout biology. Let's first of all talk about these things called

510
00:40:48,000 --> 00:40:52,000
determinants. And the notion here is that cells become

511
00:40:52,000 --> 00:40:57,000
different because of what they inherit. And

512
00:40:57,000 --> 00:41:01,000
I've drawn for you here, and this is number 21 on your

513
00:41:01,000 --> 00:41:05,000
handout, I've drawn for you here a cell, this blue thing

514
00:41:05,000 --> 00:41:10,000
with squares in it. The squares are determinants,

515
00:41:10,000 --> 00:41:14,000
and determinants are some kind of regulatory factor. They may be one

516
00:41:14,000 --> 00:41:18,000
regulatory factor, maybe more than one regulatory

517
00:41:18,000 --> 00:41:23,000
factor. They may be transcription factors. They may be splicing

518
00:41:23,000 --> 00:41:27,000
factors. They may be micro-RNA's. They may be all the things we've

519
00:41:27,000 --> 00:41:32,000
talked about in previous lectures, but I've drawn them as squares.

520
00:41:32,000 --> 00:41:35,000
And here's a cell with those little squares. And I've drawn it so that

521
00:41:35,000 --> 00:41:39,000
all the squares are on one side and not the other. And

522
00:41:39,000 --> 00:41:43,000
of course, you're sitting there asking, how did the squares get on

523
00:41:43,000 --> 00:41:47,000
one side but not the other? And that is a really good

524
00:41:47,000 --> 00:41:51,000
question. And I'm not going to tell you how to get

525
00:41:51,000 --> 00:41:55,000
on one side but not the other. But there is a whole system in the cell

526
00:41:55,000 --> 00:41:59,000
of pulleys using things like microtubules where specific squares,

527
00:41:59,000 --> 00:42:03,000
specific molecules, can actually be pulled to one side of the

528
00:42:03,000 --> 00:42:06,000
cell or the other. And then, you're going to ask me,

529
00:42:06,000 --> 00:42:10,000
well, how do they know which side of the cell to move to?

530
00:42:10,000 --> 00:42:13,000
And that's another great question that I'm not going to answer. But

531
00:42:13,000 --> 00:42:16,000
suffice to say there is a whole molecular machinery that can move

532
00:42:16,000 --> 00:42:20,000
regulatory molecules to different places in the cell. But

533
00:42:20,000 --> 00:42:23,000
let's go back to our cell that's got squares on one side and not on the

534
00:42:23,000 --> 00:42:27,000
other. When it divides, it gives rise to a cell that's got

535
00:42:27,000 --> 00:42:30,000
lots of squares, lots of determinants,

536
00:42:30,000 --> 00:42:34,000
and another cell that doesn't have any.

537
00:42:34,000 --> 00:42:38,000
The cell with the determinants goes on to make cell type one because it

538
00:42:38,000 --> 00:42:42,000
has a specific set of regulatory factors. The cell without them goes

539
00:42:42,000 --> 00:42:46,000
on to make another cell type. It's not that it doesn't have any

540
00:42:46,000 --> 00:42:50,000
regulators; it just doesn't have the ones in the squares. So,

541
00:42:50,000 --> 00:42:54,000
cells are different because of what they inherit. Here is a fantastic

542
00:42:54,000 --> 00:42:58,000
example. These are early worm embryos, early embryos

543
00:42:58,000 --> 00:43:02,000
of [scientific name]. We mentioned this last time that

544
00:43:02,000 --> 00:43:06,000
Professor Horvitz in the biology department got the

545
00:43:06,000 --> 00:43:10,000
Nobel Prize for it several years ago. And this is an example of

546
00:43:10,000 --> 00:43:14,000
determinants moving to different cells during development. So,

547
00:43:14,000 --> 00:43:19,000
the top row are cells that have been stained for their nuclei. And

548
00:43:19,000 --> 00:43:23,000
you can see one cell, two cell, and 32 cell stage embryo. These bottom

549
00:43:23,000 --> 00:43:27,000
pictures are florescent pictures of things called pea granules. These

550
00:43:27,000 --> 00:43:32,000
are determinants. And you can see even at the one cell

551
00:43:32,000 --> 00:43:36,000
stage, there are all located on one side of the cell. At the two cell

552
00:43:36,000 --> 00:43:41,000
stage, they all go to one of the two cells. And at the 32 cell stage,

553
00:43:41,000 --> 00:43:45,000
they are all in the cell over here. And those cells or that cell is

554
00:43:45,000 --> 00:43:50,000
going to give rise to the egg and sperm of [scientific name]

555
00:43:50,000 --> 00:43:55,000
, and those pea granules are determinants for the germ cells.

556
00:43:55,000 --> 00:43:59,000
Here's the other big thing. Cell-cell signaling: cells

557
00:43:59,000 --> 00:44:04,000
may secrete an inducer. This is a ligand. Remember signal

558
00:44:04,000 --> 00:44:08,000
transduction that you talked about in cell biology II?

559
00:44:08,000 --> 00:44:13,000
Those same ligands that are secreted by cells bind to receptors

560
00:44:13,000 --> 00:44:18,000
on target cells. Receptor ligand interaction leads to activation of

561
00:44:18,000 --> 00:44:22,000
signal transduction pathways, again, from cell biology II. And

562
00:44:22,000 --> 00:44:27,000
that over time can change the genes that a cell is expressing and

563
00:44:27,000 --> 00:44:32,000
changed the fate of the cell. So, we call these things inducers

564
00:44:32,000 --> 00:44:36,000
because of the specific assays involved. But really,

565
00:44:36,000 --> 00:44:40,000
they're ligands, often proteins, sometimes lipids, that bind

566
00:44:40,000 --> 00:44:44,000
receptors, activate signal transduction, and change cell fate.

567
00:44:44,000 --> 00:44:48,000
This is number 23 on your handout. So, induction: a process by which

568
00:44:48,000 --> 00:44:52,000
cells become different because their neighbors tell them to do so,

569
00:44:52,000 --> 00:44:56,000
and a variation of induction, oh, here's an example of induction, sea

570
00:44:56,000 --> 00:45:00,000
urchin embryo, the induction is everywhere.

571
00:45:00,000 --> 00:45:04,000
But I've picked this one example. Sea urchin embryo goes on through

572
00:45:04,000 --> 00:45:08,000
time to make this little thing called a pluteus larva. If you

573
00:45:08,000 --> 00:45:12,000
remove the bottom half of the embryo, it goes on. The rest goes on to

574
00:45:12,000 --> 00:45:17,000
make a kind of a round thing with lots of cilia sticking out. And

575
00:45:17,000 --> 00:45:21,000
you can take four little cells that were right on the bottom of the

576
00:45:21,000 --> 00:45:25,000
normal embryo called micro-mirrors and stick them back on this top half

577
00:45:25,000 --> 00:45:30,000
of the embryo that didn't make a normal one.

578
00:45:30,000 --> 00:45:34,000
And it will restore a pretty normal embryo. And it's not that the red

579
00:45:34,000 --> 00:45:38,000
cells have made all the parts of the embryo that we're missing,

580
00:45:38,000 --> 00:45:42,000
or the parts of the larva that were missing. It's that those red cells

581
00:45:42,000 --> 00:45:46,000
have sent out a signal, and that signal has told other cells

582
00:45:46,000 --> 00:45:50,000
what to become. And in the case of the sea urchin,

583
00:45:50,000 --> 00:45:54,000
part of that signal is something called the delta protein. This is a

584
00:45:54,000 --> 00:45:58,000
micrograph of the a sea urchin embryo at a very early stage,

585
00:45:58,000 --> 00:46:02,000
and this brown-purple group of cells here are those cells that contain

586
00:46:02,000 --> 00:46:06,000
the delta protein. These are the micro-mirrors,

587
00:46:06,000 --> 00:46:10,000
and these are involved in inducing the rest of the embryo to become

588
00:46:10,000 --> 00:46:14,000
what it does. Now, inducers, ligands, can be tricky.

589
00:46:14,000 --> 00:46:18,000
They can act in different ways at different concentrations. And

590
00:46:18,000 --> 00:46:23,000
this is one of the big questions of biology. How do they do this?

591
00:46:23,000 --> 00:46:27,000
So, for example, if you have a lot of an inducer,

592
00:46:27,000 --> 00:46:31,000
it may tell cells to become cell type one. If you have a little bit

593
00:46:31,000 --> 00:46:35,000
of an inducer, it may tell cells to become cell

594
00:46:35,000 --> 00:46:40,000
type two. And we'll talk about in a

595
00:46:40,000 --> 00:46:44,000
subsequent lecture the molecular basis for this. So,

596
00:46:44,000 --> 00:46:49,000
an inducer that can induce different fates at different concentrations is

597
00:46:49,000 --> 00:46:52,000
terms a morphogen --