NOVA explores the ground-breaking experiments that led to the discovery of a tiny sequence of molecules—and more clues to the mystery of how a complete baby develops from a single cell.
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00:00Tonight on Nova, during the nine months that this baby was inside her mother's womb, a remarkable series of events unfolded.
00:14Weighing seven pounds now, this child started as a single cell, smaller than the head of a pin.
00:20Inside that cell were the instructions for the making of this unique individual.
00:25How can you get a whole baby from one single cell?
00:30The study of this microscopic worm and of this tiny fly might provide keys to unlock the mystery of how a living creature is created.
00:39The stakes are very high.
00:41This research might lead to a better understanding of why much later in life some cells become cancerous and why sometimes things go wrong during pregnancy.
00:51Tonight on Nova, how babies get made.
00:59Major funding for Nova is provided by this station and other public television stations nationwide.
01:10Additional funding was provided by the Johnson & Johnson family of companies, supplying health care products worldwide.
01:19And by Allied Signal, a technology leader in aerospace, electronics, automotive products, and engineered materials.
01:49A newborn baby, perfect and complete.
01:54Virtually all of the body's complexity is present, seen in the details of the hands, of the face, in fact, in all of the body's organs.
02:04What lies ahead is growth and modification, but the detailed patterns of the body are already permanently set in place.
02:14Just how all of this develops from a single fertilized egg is the central puzzle of modern biology.
02:20When solved, it will describe not just how human babies are made, but all living creatures.
02:27If you trace back the development of a human baby, most of the body's complexity is apparent as early as seven months before birth.
02:37The key aspects of development all took place in the first two months as an embryo.
02:42That order emerged from a ball of thousands of cells, which in turn developed from just one.
02:53In the earliest stages, all vertebrate animals, those with a backbone, begin their development like this.
03:02The first cells divide and divide, producing a hollow ball of thousands of cells.
03:08Then, as if on cue, part of the ball buckles inwards and cells pour into the middle to start forming the internal parts.
03:20The surface layer of the embryo rolls up into a tube, creating the spinal cord and brain.
03:28Inside, internal organs form.
03:36A heart beats. Blood flows.
03:44In this case, after a few weeks, a newt has been made.
03:49In fact, in the very earliest stages, all vertebrate embryos look strikingly the same.
03:58These four embryos are from quite different animals.
04:02As they develop, only one will become a human fetus.
04:11Their differences show as they get further along in their development towards becoming a fish, a salamander, a chicken, or a human.
04:24That completely different animals start out as almost identical-looking embryos suggests that they may not be so different after all.
04:33Nature makes creatures that are varied in form and size, and yet different as they are as adult animals.
04:43They all must pass through very similar stages in their earliest growth.
04:48But more surprising, given the exquisite precision that's required for the task, is the fact that development works at all.
04:56There seem to be two important aspects to development.
05:00One is the extraordinary success rate and precision of the process, and the other is the flexibility of the process.
05:07The flexibility is most easily demonstrated by experiments where you do what seems to be enormous damage to the embryo,
05:14and yet it's able to repair that damage and still develop, in many cases, into a fairly normal adult organism.
05:22This flexibility is clearly helpful for an early embryo's survival.
05:27The cells of the earliest embryonic stages can withstand an incredible range of harsh conditions.
05:33Here under the microscope, a mouse embryo made up of two cells is actually being pulled in half.
05:41Each half of the embryo will recover, and identical twin mice will form.
05:47Sometimes this happens spontaneously in nature, producing identical twins, or even triplets like these.
05:54The embryo and their mother's womb split into three pieces.
05:58Since this happened early enough, each separate cluster of cells retained the ability to go on.
06:03They develop normally, emerging as precisely identical-looking human beings.
06:09In another case, up to 90% of an early mouse embryo can be destroyed, and yet recover and develop to produce a perfectly normal mouse.
06:22Instead of destroying cells, more can be added.
06:26One of these embryos would have become a black mouse, the other a white mouse.
06:31But when fused, the resulting ball of cells develops normally,
06:36producing a hybrid mouse called a chimera.
06:39Its whole body is a mixture of black and white cells, not just in the skin, but everywhere.
06:46This mouse has four parents instead of two.
06:52Embryos survive other kinds of harsh treatment.
06:55As the temperature drops to 31 degrees below zero, ice crystals envelop this embryo.
07:06This baby boy, born in 1985, was once deep frozen.
07:11As an embryo, he was stored at minus 320 degrees Fahrenheit in liquid nitrogen,
07:16thawed out, and implanted into his mother's womb.
07:22Even more remarkably, some animals have their own methods of storing an embryo, but at body temperature.
07:30A kangaroo usually gets pregnant again immediately after giving birth,
07:34while its baby nurses, a new embryo starts to grow.
07:38But then, as if by magic, the embryo is stopped in its tracks.
07:42This normally rapidly dividing ball of cells is restrained for months while the baby feeds.
07:48Once the baby is weaned, the new embryo starts to grow again.
07:54And one month later, another baby kangaroo is born.
07:59Embryos can even survive within a foreign species.
08:03This horse has just given birth to a zebra.
08:07As an embryo, the zebra colt had been successfully implanted into its surrogate mother.
08:12Despite being made of foreign tissue, it was not rejected.
08:21In fact, all of us were once foreign tissue in our mother's womb.
08:25Even an embryo developing in a mother of its own species, like this human one in the uterine tube,
08:30is made of partly foreign tissue.
08:32The cells of the embryo originate from both father and mother,
08:36so in a sense it is an alien residing in the womb.
08:39Yet the mother's body does not reject it.
08:42In pregnancy, the immune system of both mother and baby are specially modified to survive the experience.
08:48An early embryo can be damaged, split, frozen and thawed, and yet recover.
08:53But in the long journey that lies ahead, it will have to give up this flexibility forever.
08:58About one week after conception, the cells of the human embryo begin to specialize.
09:04What one wants to know is how one goes from the egg, the fertilized egg, which is one cell,
09:09to something like this.
09:12What one wants to know is how one goes from the egg, the fertilized egg, which is one cell,
09:17to something, someone like yourself, which is millions and millions of cells,
09:22different kinds of cells, and they're all arranged in a rather well-defined pattern.
09:29This dividing ball of cells is approaching the first major step in which cells specialize and form patterns.
09:36The hollow ball buckles in a specific place.
09:39This will become the tail of the animal.
09:42Cells stream into the interior.
09:45Where they contact the opposite side, a mouth will eventually form.
09:49This rearrangement of cells is a critical process for embryos.
09:53It's called gastrulation.
09:56The embryo sort of invaginates, so if it's a hollow ball,
09:59it's as if you were to push your fist in through the ball,
10:02and so the edges of the ball closed around your wrist,
10:04so the embryo actually sort of turns itself almost inside out.
10:07And in doing that, it creates a new layer of cells inside,
10:10and a hole, of course, called the blastopore.
10:14And that large-scale tissue movement yields a sort of multi-layered embryo.
10:20And once that's happened, each layer of the embryo then has a different fate.
10:29Gastrulation divides the embryo into three distinct layers.
10:33The outer layer, the ectoderm, is fated to become the nervous system
10:37and the surface of the animal.
10:42The middle layer, the mesoderm, will make the tissues
10:45that connect the outside to the inside.
10:52And the inner layer, the endoderm, gives rise to most of the internal organs.
10:58In the human embryo, gastrulation happens at about two weeks.
11:03Over one-third of human embryos never reach gastrulation
11:06or undergo it incorrectly.
11:08It's a precise and delicate process,
11:10a crucial event for the success of all embryos.
11:14If gastrulation happens in more than one place, a double embryo is made,
11:19and Siamese twins joined or even sharing internal organs may result.
11:24It's not birth, death, or marriage which is the most important event in your life,
11:27but gastrulation.
11:28And it is a very important event in early development
11:31because you get enormous changes in the location of cells in the early embryo
11:36so they get put in the right place so that organs can then really begin to develop.
11:42With gastrulation, cells rapidly lose their flexibility.
11:46They begin to differentiate to become committed to specific fates.
11:52These are early frog embryos.
11:56About five hours or so ago, they were single fertilized eggs.
12:00And in that period, they've divided until there's about a thousand cells here.
12:04Now, they look all the same from the top here.
12:07If you turn them over, you can see that, in fact, some of the cells at the bottom are white
12:12and the top cells have pigment in them.
12:16Under normal circumstances, if you leave these embryos alone,
12:19the cells at the bottom, underneath here, the white ones,
12:23will develop into part of the gut only.
12:28But what if I move individual white cells like these to another region of the embryo
12:33and place them amongst cells that are destined to become other organs, such as brain?
12:38Will this white cell still become gut or will it now change into brain?
12:44It all depends when it's done.
12:46At this stage, the white cell is changed by its new environment.
12:50It now becomes brain and other tissues.
12:53But just three hours later, this white cell is now committed to being gut only.
12:58Moving it to its new location has no effect
13:01because it actually finds its way back to the correct place in the embryo and develops into gut.
13:07Organ Development
13:12Organs develop according to a precise schedule.
13:17After gastrulation, the outer layer, the ectoderm, rolls up to produce a tube,
13:24the neural tube, which makes the brain and spinal cord.
13:37Muscle
13:43The middle layer, the mesoderm, goes on to produce little blocks of muscle,
13:48which start to twitch.
13:57Now, cells are visibly different.
14:01Specialized muscle cells in the heart pump specialized blood cells.
14:08The ancestors of these cells were capable of generating any kind of cell,
14:13even of founding a whole embryo.
14:16Now, the cells that go into making a structure like the eye
14:19seem to have made irreversible choices.
14:23In the frog embryo, these developmental choices are made over the course of a few days.
14:29This is what the embryos will become in three or four days.
14:32These are the early swimming tadpoles of the frog,
14:34one looked at from the side and one looked at from underneath.
14:37We can see in this one the developing gut, which is all coiled up inside the abdomen,
14:42and the eye.
14:44And on the one that looked at from the side, you can see the brain and the spinal cord,
14:48which is this gray line running down here.
14:52Now, if I increase the magnification,
14:56we can see many differentiated cell types.
15:01These black things here are pigment cells in the skin.
15:04We can see the developing heart, which is this muscular pump.
15:08And so there are obviously very many differentiated cell types present
15:12at these later stages of embryogenesis.
15:15The process of specialization takes the frog embryo only a short time.
15:20In a human embryo, it is a matter of weeks and months.
15:25This is a human embryo after five days.
15:28It is a compact cluster of cells no bigger than the original egg.
15:34After about ten days, the embryo is firmly implanted in the lining of the uterus,
15:39still barely visible to the naked eye.
15:43Soon afterwards, gastrulation will begin.
15:50After two weeks, the embryo is elongated.
15:56At the top is the structure which will become its head and brain.
16:01At four weeks, the embryo has arm buds.
16:07It has the beginnings of eyes.
16:15At seven weeks, the internal organs are visible.
16:19The embryo has clearly defined fingers that move.
16:25Less than one quarter of the way through its developmental journey,
16:29the embryo has already come far,
16:31from one fertilized egg cell to millions of specialized cells.
16:36What creates this variety of cell types?
16:39How does one cell become different from another?
16:43This is one of the central questions that intrigues biologists studying development.
16:48The trick has been to find an animal simple enough
16:51to let scientists watch each step in the process.
16:54If you ask how many cells do you and I have,
16:57the answer is something on the order of a million million.
17:01To begin to think of describing all of these cells,
17:04let alone studying them in some detail, is almost unimaginable.
17:08Whereas if we take an animal that has fewer than a thousand cells,
17:11we can really look at it in great detail.
17:15We actually study a worm.
17:17It's a very small worm, it's a microscopic animal,
17:20it's only one millimeter in length.
17:22And the features of this worm are very much like the features
17:25of the larger animals that we're used to.
17:28It has many of these different cell types,
17:30a nervous system, a musculature, gut, gonad, and so on,
17:34but it has only very few cells within its body.
17:38These circles mark individual intestinal cells
17:41of the immature C. elegans worm,
17:43the ability to watch these and the other cells of the worm develop
17:46allows biologists a unique opportunity.
17:49The simplicity in the number of cells
17:52and the fact that the animal is transparent
17:54has allowed us to look inside it while it develops
17:58and follow this development from one cell to two to four and so on,
18:03all the way up to the 959 in the adult.
18:07Biologists, during five years of painstakingly careful research,
18:11simply watched worm after worm grow.
18:14They observed and recorded what happened to each cell,
18:17from the initial fertilized egg through the larval stages
18:21and on to the adult form.
18:23Since the entire process is the same from one worm to the next,
18:27researchers were able to put together a developmental map.
18:31Like a family tree, the map shows the division of each cell into two,
18:35tracing the series of divisions from one generation to the next
18:39until all of the cells have reached their final stage of development.
18:44For example, this branch originated as a single cell.
18:48Following the map, it can be shown that a few of its descendants
18:51became adult muscle cells.
18:53Others took on a variety of different specialized functions.
18:58Through this research, the C. elegans worm
19:01has become one of the best understood living structures in the world.
19:06We know this animal inside and out.
19:08We know every cell in its body.
19:10We know where it's come from.
19:12We know where it's going.
19:14We've been able, in fact, to determine the entire history
19:18of every single cell in this animal,
19:20and what that makes possible now
19:22is a study of the factors that influence what these cells do,
19:26what each cell does at different times during development.
19:30Studies of the C. elegans worm have shown how it is
19:33that cells develop to become different from one another.
19:37There appear to be three general mechanisms.
19:40The first involves a single cell
19:42that contains different components that are unevenly distributed.
19:46When it divides, its two daughter cells,
19:48because of their components, are then different from each other.
19:53The second mechanism involves a set of identical cells.
19:56They communicate with each other,
19:58probably through chemical signals,
20:00as they compete to develop into one of a few potential types.
20:06The third mechanism involves a group of similar cells
20:09that are influenced by a cell of a different type,
20:12which is sending out a signal.
20:16That signal determines the developmental fate of these cells.
20:21So we see really three different kinds of mechanisms.
20:24We see single cells dividing,
20:26and what's in them is what makes them different.
20:29We see cells, in a sense, fighting it out amongst alternative potentials
20:33to decide which will do one thing and which will do another.
20:37And we see cells sitting and waiting and listening to other cells,
20:41which will tell them what to do.
20:46But understanding how cells form different types
20:49doesn't explain how a baby emerges
20:51from that initial ball of undifferentiated cells.
20:56The embryo also must organize its cells
20:58into the patterns that make up organs and body parts.
21:02Even if you know how cells become different,
21:05it doesn't tell you how you get patterns.
21:07And, for example, if you think of your arm and you think of your leg,
21:10it's the same cell types in each.
21:13Muscle, cartilage, bone, the cells that make up the skin.
21:17And yet your arm's quite different to your leg,
21:19and that's a problem of pattern formation.
21:21There's a problem of spatial organization of cell differentiation.
21:25And I think one can see this quite clearly
21:27if I compare myself to a chimpanzee.
21:30As far as I know, there's no cell type that I have
21:32that the chimpanzee doesn't have,
21:34and there's no cell type that the chimpanzee has that I don't have,
21:37and yet I came to be very different from a chimpanzee,
21:39and I think that's about spatial organization rather than cell types.
21:43In fact, all higher vertebrates
21:45share basically the same types of specialized cells.
21:48For example, blood cells, skin cells, or nerve cells.
21:52It's the arrangement of those cells
21:54that distinguishes one animal from another.
21:56But how do those patterns of cells form?
22:03This is the sea animal, Hydra.
22:05Its ability to maintain body pattern is so strong
22:08that it can be completely mashed up into a pulp.
22:14And yet, given sufficient time,
22:19the cells will reassemble themselves and restore the correct pattern.
22:27In the normal development of higher vertebrates, like the chick,
22:31cells also know where they belong.
22:34For example, at a certain point,
22:36cells commit to being part of a wing or a leg.
22:39But which part? The cell will specialize further.
22:42Cells remember that they belong to the leg as distinct from the arm.
22:48And so, for example,
22:50if you take cells from the very early leg bud
22:54and put them into the wing bud in the chick,
22:57they behave according to the position that you put them into the wing bud,
23:01but remember themselves as leg.
23:03So if you take cells that would normally give rise to the thigh
23:08and graft them to the tip of the developing wing,
23:12then they now develop as a toe
23:15because they take on a new position that is at the tip of the limb,
23:18but they remember that they are leg and so develop as a toe.
23:25So first a cell is committed to being part of a leg.
23:30Its next decision is whether to become thigh versus toe.
23:36And that depends on where the cell is along the limb.
23:39But how does the cell know where it is?
23:42One way of thinking about it
23:45is in terms of what one might call positional information.
23:49That is that you can make a very wide variety of patterns
23:54using the following principle.
23:56First of all, you tell the cells where they are
23:59or the cells learn where they are
24:01rather as in a coordinate system.
24:03Or, for example, if you imagine people in a stand,
24:06you know, those flash card patterns you see before match of the day
24:10or you've seen before the Olympics.
24:13Each person knows what to do at a particular position
24:16because they know their position
24:18and what they've got to do in that position.
24:20An enormous number of nature's patterns
24:23might be built with such a simple principle.
24:26Like these performers, the cells in a developing limb
24:29need to know where they are
24:31and behave in an appropriate way
24:33to become part of an elbow or a toe.
24:36But how do cells determine their position?
24:41One way for a cell to measure its position is by a chemical signal.
24:45The block at the lower left is exuding an invisible
24:48but powerful chemical attractant.
24:50These single cells are clustering towards the signal from all directions.
24:57In fact, these primitive single cell creatures
25:00also find each other chemically attractive
25:03and swarm together to form a slime mold.
25:16Such spectacular feats of one of nature's most simple forms of life
25:21can provide clues about how cells might build
25:24more complex patterns in higher animals.
25:29In multicellular animals, like the worm C. elegans,
25:33there is also evidence that cells are communicating with each other.
25:37We have seen that one kind of cell,
25:39sending out a signal, probably chemical,
25:42can affect the development of other cells.
25:45This same mechanism could also create patterns.
25:48For example, when the signal from the top cell
25:51reaches the group of identical cells,
25:53the strength of the signal will be felt differently by each of them.
25:57Since each cell feels the signal to a different degree,
26:00based on its position,
26:02it will become one of three different cell types.
26:06This graded signal has set up a pattern among the cells.
26:10So in a sense, what we're seeing is a single cell
26:13controlling spatial patterning.
26:16One cell sends a graded signal,
26:19and that graded signal results in three different fates
26:22in different positions in the animal.
26:25In theory, at least, in the limb of the developing vertebrate,
26:28there may also be a chemical gradient to which cells could respond,
26:32telling them whether to become phi or tau.
26:36Certainly, some chemicals have a spectacular effect.
26:40The salamander has an unusual ability to regenerate some body parts.
26:45This makes possible intriguing studies
26:47of the effects of chemicals on limb development.
26:50Normally, if a hand is cut off,
26:52the remaining cells will regenerate the missing part.
26:56However, if the salamander receives a dose of the chemical vitamin A,
27:00the cells of the growing limb get confused
27:03and replace more than was missing.
27:05A whole new arm instead of a hand.
27:10In the development of a human being,
27:12the formation of body patterns is vulnerable as well
27:15to the presence of chemicals.
27:17In the normal uterine environment,
27:19the developing embryo must be protected from chemical disturbances
27:23which lead to deformity.
27:25The most vulnerable time is between 15 and 60 days of gestation,
27:29as body patterns and organs begin to form,
27:32and when many women don't even know they're pregnant.
27:36Drugs, in rare instances even over-the-counter drugs,
27:39can affect the embryo during this time.
27:42One dramatic example was thalidomide,
27:44a mild sedative taken by some pregnant women in the early 1960s.
27:49Their babies were born with severe deformities.
27:52Clearly, chemicals affect how cells fall into patterns.
27:56After the first two months of development,
27:59the major patterns of the human form have been established.
28:02Even after birth, the body continues to grow.
28:05Somehow it manages to maintain correct proportions,
28:08of the arms, for example.
28:12I'm always amazed by that,
28:14that our arms do end up the same length
28:17because they start off very small,
28:20they're quite independent one from the other,
28:23and it's really like sending up two projectiles,
28:26two rockets, and they reach exactly the same height,
28:29well, very nearly the same height,
28:32after, what, 15 years or 20 years.
28:35I think it's astonishing that growth is that,
28:38turns out to be that precise.
28:42Precision isn't just a matter of cells growing correctly.
28:45Cells also have to die or stop growing on cue.
28:50In adults, red blood cells are dying
28:53and being replaced at an enormous rate,
28:56two and a half million cells every second.
29:02In the embryo, blocks of cells in the limb buds die on schedule
29:06so that fingers and toes won't be webbed.
29:13In the course of an embryo's development,
29:15a number of events must be regulated in concert
29:18in order for cells to grow, die, specialize, and form patterns.
29:23Of all the stages an animal goes through,
29:25it is this one which requires the most precise control
29:28over cell growth and specialization.
29:31The extent of this control has been demonstrated
29:33in one striking experiment.
29:35These innocent-looking cells are, in fact,
29:37a potentially deadly kind of cancer cell called teratoma.
29:41They cause bizarre tumors made up of bone cells,
29:44skin cells, hair cells, in fact, of all cells at once.
29:48They are completely unruly.
29:52In this experiment, these cancer cells are being injected
29:55into the middle of a mouse embryo.
30:08But the embryo doesn't die.
30:12It develops normally and produces a perfectly healthy mouse,
30:17a mouse which doesn't have cancer.
30:19And yet those cancer cells have clearly played their part
30:22in making the mouse.
30:23All the black parts of the mouse in the skin, hair, and organs
30:26are descendants of those cancer cells,
30:29even one of the two eyes.
30:31But they are no longer cancer cells.
30:33Instead, they've been tamed and forced to specialize
30:36and to become part of patterns in the developing organism.
30:39The diseased cells have been brought under control
30:41by their surroundings of other normal embryonic cells.
30:46Time after time, skirting disaster after disaster,
30:49a single fertilized cell grows into a fully developed organism.
30:56As they develop, these four embryos will share many things.
31:00They will all cleave and go through gastrulation.
31:03But one becomes a fish, one a frog,
31:06one a mouse, and one a man.
31:09Science must explain not only why they are similar,
31:13but why they are different.
31:17The explanation for that must lie in the genes.
31:22The fact that embryo after embryo does develop precisely in the right way
31:26suggests that we're not dealing with some sort of serendipitous environmental factor,
31:31that there has to be something built into the genes themselves
31:34which ensure the realization of the right program,
31:37time after time, at the level of the cell.
31:45As a human egg erupts from the ovary,
31:47it's already carrying genes from the mother.
31:56The genes of the father are contained in the sperm.
32:00At the moment of fertilization,
32:02the genes converge to form the unique nucleus of the first embryonic cell.
32:07In humans, this nucleus contains 46 chromosomes,
32:1123 from the mother and 23 from the father,
32:14all of which must be copied every time a cell divides.
32:18Each chromosome contains thousands of genes,
32:21genes which instruct the embryo to become a man and not a mouse,
32:25a frog and not a fish.
32:28As cells of an embryo divide and eventually become specialized,
32:31they lose the ability to become any kind of cell.
32:34Is there a change in the chromosomes of these cells?
32:37Are genes being lost?
32:40In plants, it's easy to show that genes are not being lost.
32:44These are fully grown potato plants.
32:48Yet by taking a bit of the leaf
32:51and separating it into individual cells
32:54and growing the cells in culture,
32:58one specialized leaf cell can produce a whole potato plant.
33:03So each cell must retain all the plant's genes.
33:09It's more difficult to prove this in animals,
33:12but the British scientist John Gurdon
33:14showed that animal cells keep all their genes throughout development.
33:19In a classic series of experiments in the 1960s,
33:22he took a fully specialized intestine cell from a white tadpole,
33:26broke it open, removed the nucleus from that cell,
33:29and inserted this package of genes into a newly fertilized green frog's egg,
33:34whose own nucleus had been killed.
33:37The green frog's egg now had the nucleus,
33:39the instructional genes of a white tadpole's intestine cell.
33:44If that set of genes was complete,
33:46it should be able to instruct the embryo to become a white tadpole
33:49rather than a green tadpole.
33:52But if in the process of development
33:54the original white tadpole nucleus had lost genes,
33:57it would go disastrously wrong.
34:00The experiment was done hundreds of times,
34:02and in a few cases it worked,
34:04producing white tadpoles,
34:06which then grew up into white frogs.
34:09Gurdon had proved that a specialized cell in the tadpole's body
34:13still had all of the original genes locked up in its nucleus.
34:17One cell could provide the genetic blueprint for the entire animal.
34:23Several experiments over the past 10 and 20 years
34:26have indicated most likely that all the cells
34:29contain identical genetic information.
34:32And so it's not so much qualitatively
34:34what bits and pieces of chromosome they have,
34:37but it's what genes are on and off.
34:41Among the genes laid out on each chromosome,
34:44appropriate genes turn on to make proteins
34:47that the cell needs at the time.
34:49Each gene codes for one type of protein,
34:52and the amino acids that make up that protein
34:54are strung together only when the gene gets turned on.
34:58Active genes can be seen at work on these chromosomes.
35:03The puffed areas are the active genes,
35:05genes which are making proteins.
35:08The other parts are shut down.
35:11It is the switching on and off of its genes
35:13that determines how a cell behaves.
35:17These are cancer cells magnified several thousand times.
35:21It is now thought that in cancer cells,
35:23genes which should be off have in fact been switched back on.
35:28For example, normal cells know when to stop growing,
35:31but when cells turn cancerous like these, they don't.
35:36It's not that they grow particularly fast,
35:38but they don't stop growing when they should.
35:43In cancer cells, the genes which control cell division
35:46should be turned off, but are not.
35:49Similarly, there may be genes switched on in some cancer cells
35:52which enable a cancer to move throughout the body.
35:56This ability to move is also seen in embryonic cells
35:59like the primitive sex cells.
36:02At a critical time in development,
36:04their genes for movement switch on.
36:06And all of a sudden, they galvanize into action
36:08and start to crawl.
36:10And they leave the gut, and they crawl up the piece of tissue
36:13connecting to the rest of the body,
36:15and as they do so, they crawl through the tissues of the embryo.
36:18So they push the other cells out of the way.
36:20And they behave very much like tumor cells do
36:22when they become malignant.
36:24And then they crawl around a corner, and then they stop.
36:27Something also tells them to stop in the right place
36:30where the gonad will form and where the gametes,
36:33the sex cells of the adult, will eventually differentiate.
36:36So there's some cell types in the embryo exhibit properties
36:40which are very similar to malignant tumor cells in the adult.
36:44And so the hypothesis is that in a tumor, as a tumor grows,
36:50some of the cells in that tumor
36:52suddenly accidentally reawaken these genes.
36:55If those genes accidentally reawakened,
36:58that cell will become motile in the adult,
37:00but out of control because there's no target.
37:06Turning on the right genes at the right time
37:09is the basis for the normal development of the embryo.
37:13This is what creates each cell's particular characteristics.
37:17There must be a control mechanism for turning on certain sets of genes
37:21in certain parts of the organism
37:23and turning off other sets of genes in the organism.
37:26And that's the mechanism we're trying to understand
37:29because that mechanism is involved in all of the special characteristics of cells.
37:34Turning on certain genes in blood cells
37:37means blood cells will have the red pigment hemoglobin in them.
37:40Turning on other genes in skin cells will make them produce hair or whatever.
37:45And the whole process has to be coordinated in a very precise way.
37:49Researchers study the chromosomes in order to understand
37:52how such a process is coordinated.
37:54They can isolate genes and try to discover what each one does.
37:58So far, a relatively small proportion of human genes
38:01has been analyzed in this way.
38:03The genetic system in a human
38:06has on the order of 100,000 genes in it.
38:09These genes form some incredibly complicated circuitry
38:13in which genes turn one another on and off.
38:16And we want to understand that system.
38:18Now, no scientist has ever understood a system
38:21with 100,000 components turning one another on and off.
38:24So instead, scientists turn to simpler organisms,
38:27in this case, a fly.
38:29You want an organism that's small.
38:31And you can see that these flies are not like your house flies.
38:35These are little guys.
38:38In this cage alone,
38:40we have probably on the order of 10,000 to 20,000 flies
38:44sitting on those plates, laying eggs, and wallowing in the food.
38:48The food is a simple mixture of molasses and a little yeast.
38:53In a few hours on those plates,
38:55you're likely to find as many as between 10,000 and 100,000 embryos.
39:01The fly is the fruit fly, Drosophila.
39:04Geneticists love it because it has relatively few genes,
39:07perhaps as few as 5,000,
39:09and because its life cycle is so short
39:11that they can monitor thousands of generations for genetic changes.
39:17Some of these genetic alterations can make enormous differences.
39:21For example, changes in head shape.
39:25At the beginning, people simply collected
39:28every strange-looking fly they saw
39:31and started keeping notes on what they had collected.
39:34These were things with changed eye color,
39:36changed pattern of bristles on the cuticle,
39:40or changed wing structure, whatever it might be.
39:43Hundreds and eventually thousands of different such flies were found.
39:47In most cases, these changes in the appearance of the fly
39:51were due to mutations which were inherited by all of that fly's progeny.
39:56And in fact, there are stock centers
39:58where thousands of different kinds of flies,
40:00all of the same species,
40:02these little changes in their structure, these mutations, are stored.
40:07This room is full of bottles of different Drosophila mutants.
40:10They all differ in some small characteristic,
40:13eye color, wing shape, and so on.
40:16The fact that they pass a particular trait onto their offspring
40:19proves that the trait is written into the fly's genes.
40:22The next question is, which genes produce which structures?
40:26Suppose you're interested in how a wing is made in the fly.
40:29It is possible to mutagenize, induce mutations in flies,
40:35and find out what genes are involved in making that wing
40:40by looking for mutations that disrupt the formation of that wing.
40:45A small change in the wing can be the result of a mutation of a single gene,
40:49of a single small piece of a gene.
40:52This is the stuff that all genes are made of.
40:54It's DNA.
40:56It provides the basic instructions for the making of proteins,
40:59and it's proteins that determine what each cell does.
41:03The letters on the top line represent the building blocks of DNA.
41:07They code for the amino acids written below them,
41:10which, strung together, make up one long protein.
41:13There may be a thousand building blocks in this one gene.
41:16A change in just one of them can ruin the protein and cause a mutation.
41:20It could be devastating to the fruit fly.
41:23It could be lethal.
41:25Studies of the Drosophila chromosomes that have undergone gene mutations
41:28show that most of the 5,000 genes have routine functions general to all cells.
41:34There are genes that encode functions that, in the field,
41:37are usually called housekeeping functions.
41:39These are genes required for cells to sort of live and breathe and eat
41:43and metabolize and do all their normal, everyday things.
41:46Usually, it appears that these genes are not the genes
41:50that control the developmental processes.
41:53In fact, there appear to be certain genes that are sort of
41:56high in some hierarchy we could construct
41:59that are central regulatory switches of some sort
42:02that control what part of a developing organism develops into what.
42:09Not all genes, then, are equal.
42:12There are master genes which, when activated, have far-reaching effects.
42:16By mechanisms now being explored,
42:19they seem to be able to turn on banks of lower genes
42:22and coordinate their activity.
42:24We really are looking at a program that's occurring at the level of a single cell.
42:29So you could really look at these master genes as programming chips.
42:33These are instructing that single cell.
42:36It's setting up a genetic program whereby the single cell
42:39is going to realize what we call a cascade of gene expression.
42:44This cascade of gene expression, multiplied over many cells,
42:48determines what kind of tissue they will form.
42:51These small stabilizers behind the fly's wings
42:54are the result of a cascade caused by a master control gene.
42:58But if that gene is mutated, a different cascade takes place,
43:02and instead of stabilizers, wings are formed.
43:07A tiny change in this master control gene
43:10completely alters the body pattern of the fly.
43:13Master genes that control body pattern are called homeotic genes.
43:18If you mutate a homeotic gene,
43:21you are likely to transform the tissues of one body segment
43:27located at one place in the fly
43:29into the tissues of another body segment normally located elsewhere.
43:33That is, in homeotic mutations,
43:35you oftentimes make the right structure in the wrong place.
43:40For example, this is a normal fruit fly.
43:43Where normally the head sprouts a tiny pair of antennae,
43:48this mutant has a pair of legs growing.
43:52Changing a homeotic gene has transformed
43:54what would have been antennae into legs.
43:58Now there's a number of things to notice about homeotic mutants
44:00immediately that are, beside the genetics,
44:03that are just astonishing.
44:05One thing is that the two ends of the fly are far apart.
44:08The head and the genitalia are at the opposite ends of the fly,
44:11and you don't have to be much of a biologist to realize that.
44:14Yet there's a mutant called tumorous head
44:16which changes the head and the antennae into genital structures,
44:20making a quite embarrassing, quite embarrassing fly.
44:25Mutations have been found in other organisms,
44:27such as the tiny worm C. elegans.
44:30These mutations not only control where features develop,
44:33but also when they develop.
44:35As in the fruit fly, there are mutants in C. elegans
44:39that result in homeotic changes
44:42that cause one body part to be produced
44:44in addition to where it normally would be produced someplace else.
44:48But what's remarkable is that in the nematode, in C. elegans,
44:52we have been able to identify mutants
44:55that not only cause changes in position in body parts,
44:59but changes in the time in which the body parts are generated.
45:04For example, there are mutants that affect
45:06the timing of expression of what essentially is the outermost layer,
45:09the cuticle, of the animal.
45:12Normally an adult animal has an adult cuticle,
45:15and a larval animal has a larval cuticle.
45:18But we have mutants in which a larval animal will have an adult cuticle,
45:22and we have other mutants in which an adult animal will have a larval cuticle.
45:27So what this shows is that you can control
45:29different aspects of timing independently
45:33and have different body parts developing at different rates.
45:37So just as we have genes that have been seen in both flies and worms
45:42that control the spatial positioning of certain kinds and parts of the body,
45:47we see that there are genes that control timing
45:51of particular aspects of development.
45:56In humans, the search is on for master-controlled genes
45:59like those found in flies and worms,
46:02which control the timing of development and body patterns.
46:08Minor changes in body patterns, such as extra fingers or extra toes,
46:12are fairly common birth disorders.
46:14Although partially genetic in nature,
46:16they appear to be influenced by environmental factors as well.
46:20As in the case of hairlip,
46:22these appear to be small deviations from the developmental plan.
46:26Fortunately, some of these disorders can be corrected with surgery.
46:30The developmental plan for a human face involves countless thousands of genes.
46:35But as in flies, are there a handful of master genes
46:38which dictate the basic pattern?
46:40How do we find them?
46:41There are no obvious homeotic mutants to guide us.
46:44We just do not see people with a nose
46:47in place of an ear
46:49or a mouth
46:51instead of an eye.
46:53And why we don't see them in vertebrates and man is just not clear.
46:57Maybe they're lethal.
46:59Maybe that they're slightly more complicated
47:02or they have to act in concert so that you have to mutate
47:05two or three of them to get the effect.
47:07The answer is we don't know, but in time we will find out.
47:11At the level of body pattern,
47:13humans and fruit flies may be too far apart to bear comparison.
47:17But perhaps the clues that link them are written in the genes.
47:21Modern molecular biologists can analyze genes
47:24to determine their DNA sequence,
47:26to look for patterns in the building blocks
47:28that make up specific genes.
47:30It's the master homeotic genes that really interest them,
47:33genes powerful enough to turn an antenna into a leg.
47:37As molecular biologists began working on these genes,
47:41we were, of course, looking for things
47:43that these genes had in common with each other.
47:45Even though the effect of a mutation in one of the genes
47:48might be to turn antennae into legs
47:50and in another one of the genes
47:52to make an extra set of wings on the fly,
47:55yet the basic idea of what these genes were doing
47:59was so similar in the two cases and in many other cases
48:02that we really were looking for something in common
48:05between the molecular structures of these various genes.
48:08And, in fact, we found such a thing,
48:10which is now called the homeobox.
48:13In the fly, the homeobox was a small, distinctive sequence of DNA
48:17which coded for a unique part of a protein.
48:20This sequence was found only in homeotic genes
48:22and not in ordinary genes.
48:24Was it critical for genetic control?
48:27If the homeobox was not some sort of critical component
48:32of genetic control,
48:34you would expect it to be associated with genes
48:36that simply did not have a particularly interesting function in the cell.
48:40And so far, at least in the fly, that has not been the case.
48:44Surprisingly, this critical sequence started to turn up in other animals.
48:48Virtually identical homeobox protein sequences were found in frogs,
48:52they were found in mice,
48:54and in 1984 they were found in humans as well.
48:59For an almost identical protein sequence to be found in so many species
49:03suggests it has a unique and possibly universal function.
49:08It is an awesome notion.
49:10Perhaps throughout a large part of the animal kingdom,
49:12the homeobox is always the telltale sign of a master control gene.
49:18And this proposal is based on a very simple premise,
49:22and that is that complicated processes of development
49:27are solved once in evolution.
49:29You don't just randomly solve these very integrate processes of development
49:34more than once.
49:35That makes some sense.
49:36We're talking about the coordination of many thousands of genes
49:40in a developmental circuit.
49:42And in order to do that,
49:45you have to somehow evolve a class of controlling genes, so we believe.
49:49If that's the case, you just don't expect to separately and independently
49:53evolve that kind of mechanism on many, many occasions.
49:59Insects like the fruit fly, Drosophila,
50:01and the animals which led to us,
50:03diverged 500 million years ago.
50:06For the homeobox to be handed down unchanged
50:08throughout such a long period of evolutionary time
50:11suggests that it's doing something useful.
50:14But is it doing the same thing in vertebrates as in fruit flies?
50:18That's the important question.
50:21And we still don't have an answer.
50:25If the homeobox is a component of master control genes
50:28that lay down body patterns,
50:30then it will be found working at critical times like these.
50:34During development, cells must be told where to go and what to become.
50:40From these cells, the spinal cord and vertebrae of a human being will form.
50:53If the homeobox genes are controlling the process,
50:56they might be expected to turn up here.
51:00Ever since molecular biologists found the homeobox
51:03in a number of human genes,
51:05they've been trying to understand the precise role
51:07of the homeobox in human development.
51:10At the same time, comparisons with other animals
51:13have uncovered another surprising similarity.
51:16Between genes of two very different species,
51:19humans and vertebrates,
51:21the homeobox is the only gene
51:23that can control the process of development.
51:26Between genes of two very different species,
51:29humans and the C. elegans worm,
51:32a master-controlled gene in the worm
51:34produces a protein involved in the communication between cells
51:38necessary for proper development.
51:40And this gene has been studied at the level of molecules
51:43for much the same reasons that the homeotic genes in flies
51:46have been studied at the levels of molecules.
51:49And when the DNA sequence of this gene was examined,
51:52what was found was that it was similar
51:55to the sequence of other genes that have been seen before
51:58in animals like ourselves.
52:00This is part of the protein in the worm
52:03coded for by the master-controlled gene
52:05that's involved in communication between cells.
52:10These are parts of proteins produced by human genes
52:13which play a similar role.
52:15Some components in both sets of proteins form a pattern,
52:18evidence of an underlying structural similarity.
52:21These kinds of similarities between human genes
52:24and a worm's master-controlled gene
52:26encourage researchers to look throughout nature
52:29for mechanisms of development that are basic to all life.
52:33And so what we hope is that by continuing the detailed studies
52:36that are possible of this gene in the worm,
52:39we'll be able to understand how genes like this function in people
52:44and also perhaps how genes like this may dysfunction in people
52:48to lead to certain human disorders.
52:51The study of simple organisms like the worm
52:54has led to startling discoveries about the way that cells develop
52:57and the roles genes in their protein products
53:00play in cell communication.
53:03The molecular study of the master-controlled genes in fruit flies
53:06that allow drastic mutations
53:09has led researchers to find genes of a similar structure
53:12in a wide variety of organisms, including humans.
53:17But the understanding of the human chromosome
53:20and its 100,000 genes is only just beginning.
53:23And even when understood,
53:25will not reveal all the secrets of human development.
53:30Genetics, or genetic makeup,
53:32clearly is defining to a great extent what we can develop into.
53:37We're not going to become penguins or redwood trees.
53:41We're clearly all going to become people.
53:44Yet at the same time, the genetics really lays out a blueprint.
53:48And we know from a variety of studies,
53:50for example, work on the nervous system,
53:52that the way in which we have experienced certain things during our lives
53:56can affect certain aspects of the development of the nervous system.
54:00We don't yet really know enough about development in detail,
54:04particularly in people,
54:06to know to what extent environmental influences will affect development.
54:10But it seems perfectly clear
54:12that superimposed upon that basic blueprint of the genes
54:16will be environmental influences.
54:20Science, through observation and experimentation,
54:23has uncovered a host of intriguing clues
54:26about the nature of embryos and development.
54:29That these clues come from so many forms of life
54:32shows how fundamental the questions are that we are trying to answer.
54:39But as our understanding increases, our wonder is not diminished.
54:46It is a common occurrence, and yet an awesome fact,
54:49that a human being is formed from a single fertilized egg cell.
54:55That even before being born,
54:57a baby has traveled a complex and mysterious journey.
55:02It is a journey science is striving to understand.
55:06But even when understood,
55:09it will remain a miracle how babies get made.
55:45Transcription by ESO. Translation by —
56:15Transcription by ESO. Translation by —
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