One question. Why is there such a stunning diversity of life? One answer. Evolution. Charles Darwin's brilliant theory that explains how species adapt and change. It's been called the best idea anyone ever had. But there's one big problem. How does it actually work? Thank you. Now, extraordinary science is answering that question. It is uncovering the hidden mechanisms inside creatures'bodies that can explain astonishing transformations like how birds can evolve from dinosaurs, why a fish was once your ancestor, and above all, what makes us human. Right now on NOVA, you'll find out what Darwin never knew. Major funding for NOVA is provided by the following. The tree of life on Earth is one of stunning diversity. 9,000 species of birds. 350,000 kinds of beetles. 28,000 types of fish. In many living species. And counting. And we are just one. But why is there such an amazing variety of animals? Why are there so many types of fish? So many different species of beetle? How did this extraordinary profusion of life on Earth come about? Today, we celebrate the man who would ultimately answer that question. Charles Darwin. He was born 200 years ago, and it is 150 years since he published the work that has become the bedrock of our understanding of life on Earth. What Darwin wanted to understand was how you get this extraordinary diversity of life on Earth. He was spot on. He really nailed it. Darwin's theory of evolution, his account of why species adapt and change, has been called the best idea anyone ever had. But even Darwin admitted that his work was incomplete. Vast questions were still unanswered, and the biggest question was how. How did evolution take place? He didn't know any of the mechanics of that process. He didn't understand the physical forces that would actually change the way species appeared. But today, we can answer the questions that Darwin could not. We can look under the hood of evolution and see exactly how this mysterious process gives rise to such astounding diversity. What's incredible about this time and from a scientific perspective is we're going to be able to understand that diversity and that just adds to the excitement. It doesn't demystify it, it makes it all the more magical. And this is the magic and mystery of evolution. Over eons of time, a single species gives rise to many. An ancient fish evolves to become the ancestor of all four-limbed animals, even us. And one species, our own. develops a large and uniquely complex brain, enabling us to dominate the planet. This is the search for the answers to what Darwin never knew. Darwin began his love affair with nature when he was a child. just like many of his modern followers, including evolutionary biologist Sean Carroll. I developed my interest in animals the same way I think most biologists did, which is either going out in the backyard or going to zoos. Anytime I got a chance, I'd flip over logs and look for salamanders and snakes and frogs and things like this, and I was just fascinated with their patterns and behavior. So it was with the young Charles Darwin. Young Charles liked the traits around the outdoors, he loved to collect beetles and things. He was a completely ordinary kid, and he didn't like school. In fact, he was such a poor student that his father, a rather successful physician and a pretty imposing figure, was worried about Darwin's direction in life. So his father packed him off to Edinburgh, the finest medical school in Europe, to become a doctor. But young Charles was just too squeamish. And he's really horrified by medical school. He witnessed an operation on a child, and this is in the era before anesthetics. And he just fled the operating theater, vowing never to return. Next, his father sent him to Cambridge... ...to study for the clergy. He didn't succeed at that either, but he did find his direction in life, reviving his childhood interest in nature. Darwin starts on his path to his divinity degree, and he starts to mature as a student. He becomes more serious about some subjects, particularly natural history, and he learns a lot more about botany and about geology and these things. He's becoming a pretty solid field scientist. His reputation as a naturalist gained him a spectacular invitation. Charles was offered a place on the British Navy ship, the HMS Beagle, whose mission was to survey the waters around South America. Now the captain of the Beagle wanted a well-educated scientific person aboard and a dinner companion, somebody to share a conversation with. And Darwin fit the bill perfectly. And so, Charles Darwin set off on a fateful voyage that would revolutionize our understanding of life's great diversity. The voyage of the Beagle took nearly five years. It wove its way from the Cape Verde Islands and along the coast of Brazil. It was in Argentina that he made his first important discovery. Early on in the voyage, Darwin found some amazing fossils. He dug up some skulls, some jaws, some backbones of what turned out to be giant mammals. Now, these were clearly extinct. And Darwin began to ponder what was the relationship of those fossils to the living animals of South America. Subtitles by the Amara.org community But one port of fall on Darwin's voyage proved more important than all the others. The Galapagos. This cluster of 13 isolated islands lies 600 miles off the coast of Ecuador in the Pacific Ocean. These islands are home to unusual animals found nowhere else on Earth. Penguins that live at the equator and swim in warm water, instead of the frigid seas of the South Pole. Giant tortoises that weigh up to 600 pounds. Iguanas, huge lizards that swim and dive in the sea. Everywhere else, they dwell only on land. Traveling for the first time in the Galapagos, Sean Carroll is seeing the same creatures. It so intrigued Darwin. Of all animals, I think these marine iguanas are the greatest symbol of the Galapagos, what I most wanted to see here. And to see them in their native habitat blending against that black rock, just as Darwin described it, it's an absolute thrill. It's a hideous looking creature. Of a dirty black color, stupid and sluggish in its movements. They are as black as the porous rocks over which they crawl. Darwin meticulously described the iguanas in his diary. But he was far from the scientific authority he would become. The Darwin that arrived here was not the great theorist that we know today. He was a 26-year-old collector, collecting really almost at random any kind of plants, any kind of animals, any kind of rocks. He didn't even know the meaning of what he was collecting until much later. He was also fascinated by the giant tortoises, which allowed him to ride on their backs as they slowly lumbered around. I frequently got on their backs and then, upon giving a few raps on the hinder part of the shell, they would rise up and walk away. But I found it very difficult to keep my balance. Darwin measured the creature's extreme slowness, about four miles a day, he calculated. But the local people knew something else about the tortoises. that they could tell which island any tortoise came from just by looking at its shell. Their shells differed depending on which island they lived on. Some tortoises had shells shaped like a dawn. Others had shells arcing over their heads like a satin. Others differed subtly in color, or by how much the bottom of the shell flared out. Darwin had literally been sitting on a clue, a way to understand the great diversity of life. But he didn't yet realize. Instead, Darwin turned his attention to birds. The islands were full of what seemed to be a familiar assortment of species. So he stuffed his collecting bag with what he thought were types of finches, grossbeaks, wrens and blackbirds. Darwin and the Beagle went to other ports in the Pacific, and finally set sail for home. On board, he started to sort through the vast number of specimens he had collected on the five-year voyage. But it was not until he returned to Britain that he was able to make sense of them. It began with a startling revelation. All the different birds he had collected actually were variations of a single type. He learns that those birds he had collected on the Galapagos actually represent 13 different species of finch. What misled Darwin was that they looked radically different. Some had wide, tough beaks. Others had long, slender ones. And these differences depended on which islands they lived on. Now why would that be? Why would there be slightly different birds, slightly different species, on different islands, all in one part of the world? And now thought back to the Galapagos tortoises. They too differed from island to island. His brain began racing. Thoughts are starting to crystallize, take shape in his mind, bit by bit, bit by bit. He starts this process he describes as mental rioting, just stream of consciousness where he's jotting down note after note after note, thoughts as they occur to him. And finally, they converge on this one idea. What Darwin now realized was that somehow, for some reason, species change. Originally, there must have been just one type of finch in the Galapagos, but over time it had diversified into many kinds, with different beak shapes. The same for the tortoises. One type of tortoise must have turned into many kinds, with different shells, depending on which island they lived on. With this great insight, Darwin entered dangerous new territory. The standard view at the time was that God had created every species, and that what God had created was perfect and could not change. But Darwin said no, why would the creator bother with making slightly different finches for each of these different islands that all looked alike? The prevailing view just didn't make sense. But this was only the beginning of Darwin's revolution. He turned his attention to the fossils he had collected in South America. One was of a giant sloth. Another was of a huge armadillo-like creature. These animals were extinct. But little sloths still existed in South America, and so did smaller armadillos. What could this mean? It dawned on him that they resembled each other, so what he had found in the ground were the buried ancestors of the living animals of South America. So again, here was more evidence that species changed. Somehow, these ancient giants must have been transformed into the smaller creatures we see today. But what Darwin would later find out took this idea of how species change into a completely new league. In Victorian times, scientists routinely studied life forms at the embryonic stage. How these tiny forms develop from just a single cell into an entire creature has long been seen as one of the wonders of nature. Watching a developing embryo is truly the most glorious miracle of nature. I mean, you know, no baloney. What Darwin learned from studying the embryos amazed him. In snake embryos, you could see tiny bumps, the bony rudiments of legs. But these would never develop in the adult snake. Darwin wondered, were snakes somehow descended from animals with legs? He learned that whales, which have no teeth as adults, had them as embryos. Those teeth disappeared before they were born. To Darwin, it had to mean whales were descended from creatures with teeth. But human embryos provided the most startling evidence. Under the microscope, tiny slits around the neck were clearly visible. Exactly the same structures were found in fish. But in fish, they turned into gills. In humans, they became the bones of our inner ear. Surely, this showed that humans must be descended from fish. It's an astonishing thought. I don't know about your ancestors, but mine included priests and the usual suspects. But the idea that all of us have fish in our family tree, I think it's amazing. And so Darwin arrived at an astonishing conclusion, one that would become central to his understanding of the great diversity of life. Darwin had this amazingly bold idea, the tree of life, that all species were connected. And what it meant was if you go far enough back in our family tree of humans, you'll come to fish. If you go far enough back in the family tree of birds, you'll come to dinosaurs. So that creatures that don't look anything at all like each other are actually deeply connected. No one came close to having this idea before Darwin. This seemed to be an explanation for the vast diversity of animals. Beginning with a common ancestor over time, across generations, species could change dramatically. Some might add new body features, others might drop them. Ultimately one type of creature could be transformed into something utterly different. It's a process Darwin called descent with modification. But it all begged a question. Why? What was making creatures change? Darwin needed clues. And he found them in a very surprising place. Dogs. Big, small, fat, tall. The British have long been obsessed by them. It was a full-blown love affair in Victorian England. Even Her Majesty was dog-crazy. That love affair still continues today, especially among scientists like Heidi Parker at the National Institutes of Health. So one of the most interesting things about dogs is the kind of variation that you have. And we have dogs the size of groundhogs versus a dog like Zeppy the Leonberger who can get to be the size of a mule deer. If we had that kind of size variation in humans, we would have people running around the size of Barbie dolls. In his day, Darwin knew this range of sizes hadn't come about by chance. Through a careful process of selection, dog breeders mix different dogs with different physical traits to create new forms. Darwin was intrigued by what he was seeing breeders doing with the domestic dog. They could select for individual traits like size or shape, and they could actually change their breed. The whippet, for example, had been developed to chase rabbits. It was created by mixing greyhounds for speed with terriers used to hunt small game. And then it hit Darwin. Was there a similar form of selection going on in nature, but without human interference? Could natural selection explain the great diversity of life? It was brilliant. He took something very familiar and comfortable, for example, animal breeding, and explained that the same sort of thing was going on in nature, just at a little bit different pace and with no human guy. But what could be carrying out selection in the wild? It was then that Darwin took a completely fresh look at nature. The Victorian view of nature was sentimental. Lambs lay down with lions. But Darwin's travels on the Beagle led him to a different view. For Darwin, nature was savage. Every creature was locked in a desperate struggle for survival, ultimately ending in death. The scale of death in nature is absolutely horrendous. And sometimes it's not just that there's a lot of death, but that it's very unpleasant death. But in all this brutal chaos. Darwin saw a pattern. Darwin showed that nature was a battlefield and that everything was in competition. And this brutal battle, this war of nature as Darwin described it, was actually a creative process. The pattern that Darwin saw was that the creatures that survived were those best adapted to the specific environments they lived in. For instance, some could handle extremes of climate. Others were brilliantly honed killing machines, perfect for catching the available prey. Still others were perfect to evade those who might be hunting them. But how did this harsh view of nature explain the finches on the Galapagos, where Darwin observed that the birds on different islands had different beak shapes? Somehow those different beaks must be helping the finches survive. The finches of the Galapagos Islands have beaks of many sizes and shapes. And there's a reason for that. They use their beaks as tools. Now if you think of the type of tool you would want to crush a seed that's very tough, but is the food that you really like, you'd want a beak like this, which is the type of beak the ground finch has. On an island where the only food is seeds that are hard to crack, a short powerful beak will mean a finch will survive. But on another island, the available food isn't seeds, but flowers. If you wanted to get into narrow spaces to get pollen and nectar that are very hard to get at, you wouldn't need a big strong beak, you'd need a probing beak. So on a different island where you have a different food source, you have a different beak shape. And this pattern was repeated across the Galapagos. It seems that the finches'beaks had altered to fit the diet of each particular island. And that was how one original type of finch had been transformed into many. But how had these changes come about? Here, Darwin had another clue. He could see it in his own family. As every parent knows, no two children are ever exactly the same. Charles looked different from his brother Erasmus, even though they shared the same parents. Charles'children looked a bit like him and his wife Emma. But they too looked different from each other. That was something he called variation. He realized that not every individual was the same stamped out like a toy from a press, but there was variation. He realized that variation must be the starting point for change in nature. In any generation, the animals in a litter are never quite the same. And in the wild, such a tiny variation might make all the difference between life and death. Two penguins, for instance, might differ a tiny bit in the thickness of their blubber. A big factor if you live in extreme cold. In a harsh climate, the environment will select who will live and who will die. And slowly, Darwin suggested over many, many generations, these tiny variations would allow the fit to get fitter and the unfit would vanish. These variations accumulate and eventually new species branch off. This is evolution by natural selection. It is one of the keys to how new species are formed. And so, in 1859, after years of painstaking research, Darwin finally published his masterwork, On the Origin of Species. It is still impossible to overstate its importance. It was really a quantum advance in understanding. It shook people up. It changed the way people thought. Gone was the idea that all species were created perfect and immutable, taken as an article of faith. In its place, Darwin provided a proper scientific theory based on facts and observation. It is much more than the presentation of simply the idea of natural selection. It is a vision of how evolution by natural selection works. 150 years later, his theory has stood the test of time. What's amazing is that Darwin got so much right. His ideas largely stay intact today. But Darwin himself acknowledged that there were holes in his theory. He didn't actually know how it worked. What was happening inside a creature's body that makes it change? But now, at last, modern science is providing the answers through a hidden mechanism that Darwin knew nothing about. Arizona's Pinnacardi Desert is a harsh and brutal place, especially if you're a rock pocket mouse. They're the Snickers bar of the desert. They really are. They're eaten by everything. They're probably eaten by foxes and coyotes and rattlesnakes, owls. Weighing just half an ounce, this mouse could never fight off these large predators. Its best hope for survival is camouflage. Not surprisingly, its fur matches the color of the Pinacardi rocks. But in some sections of the desert, the environment is different. Ancient volcanoes erupted and now the desert is a patchwork of dark lava and light rock. But of course, a light mouse on a dark rock is easy pickings. So something has happened that Darwin might have predicted. The mice now living on the dark rocks have evolved darker fur. Those that stayed on the light rocks remain light. Michael Nachman was fascinated. How had this happened? To find out, he first needed to catch some mice. So with Sean Carroll, he visits a line of traps he set the previous night. All of the dark ones have a white underbelly and presumably there's no selection for dark on the belly because predators are coming from above. This much Darwin could have done. Find some mice and compare the color of their fur to their environment. But Nachman can now do something that Darwin never could. He can look inside the animal's DNA. The study of DNA is one of the great triumphs of modern science. It has taken our understanding of how creatures evolve and develop to a level that Darwin could never have dreamed of. The DNA molecule is one of the real secrets of life. It's a perfect system for storing the vast amounts of information that's necessary for building all kinds of creatures. DNA consists of one long molecule spiraling around in a double helix. That helix is in turn made up of four smaller molecules, called by the letters G, A, T and C. DNA can be found in the cells of every living thing on Earth. The thing about DNA that I think is remarkable is that the molecule itself is so elegant. With a small number of letters, you can say almost infinite words. And that is the key. DNA is a code and its double strand contains all the information to make living things grow and develop. Lined along each DNA molecule are arranged special sequences of this code that form our genes. Many genes get translated into proteins. And these proteins make the stuff of our bodies. One protein makes hair. Another makes cartilage. Others make muscle. What makes DNA so amazing is that it just contains four letters. But all sorts of combinations of those four letters contains all the information for making all the creatures that are on the planet. It's a gene that determines whether our eyes are blue or not. Another gives us freckles. Another gives us dimples. But DNA has one other vital quality. It doesn't stay the same. When a baby is conceived, the fertilized egg receives half its DNA from the mother and half from the father, creating wholly new combinations. It's why we look a bit like our parents, but also different. Another way that DNA can change is mutation. Mutation is a critical ingredient in the recipe for evolution. Without mutation, everything would stay constant, generation after generation. Mutation generates variation, differences between individuals. Mutations can happen as our DNA copies itself when our cells divide and our bodies develop. An A, for instance, can be replaced by a G, or a C by a T. This can cause minute changes that no one is even aware of. But when mutations occur in the cells we pass down to our children, they can cause big changes. Like turning a light-colored mouse dark. Mutation seems to mean that something bad has happened. Well, mutations are neither good or bad. Whether they are favored or whether they are rejected or whether they're just neutral depends upon the conditions an organism finds itself. So for the pocket mouse, a mutation that caused the mouse to turn black, that is good if you're living on black rock, and it's bad if you're living out in the sandy desert. It was that mutation, the one that turned a light-colored mouse dark, that Michael Nachman was hunting for. Back in the lab, he began the painstaking business of comparing the genes of the two types of mice, trying to pinpoint any differences. Science is fun when you really don't know what you're going to find. One by one, the genes in the two mice proved identical. But then, in one gene, he found something. There were four places where the sequence of A's, T's, C's and G's were different. When a mouse is born with these mutations, its fur grows dark. And that means it can survive on the dark rocks when others would not. Here was a clear example of evolution and natural selection at work. I think Darwin would have been delighted to know that we can find the genes that are responsible for evolutionary change. And this was just one of many links that have been found between genetic mutations and evolution. Scientists can now pinpoint a range of examples of evolution in action. The colobus monkey can see in color because of a mutation in one gene. It can now tell nutritious red leaves from tough old greens. A genetic glitch gave this Antarctic fish a potent antifreeze in its blood so it can survive in the icy waters when others cannot. So powerful was this link between genetic mutation and evolutions that an idea took hold. To understand how evolution works, all you need to do is compare creatures'genes. One might think that you can understand all of evolution simply by mapping the genes of every creature. Identify all the genes, identify all the differences, and you could explain the differences between, say, mouse and monkeys and humans. So when the Human Genome Project began in 1990, the scientific world was on tenderhooks. All three billion letters of our DNA were going to be identified in order. In parallel, the DNA of some animals and plants was also being sequenced. Surely this would be a quantum leap in our understanding of how different life forms evolved. With this came another idea, that complex animals like us would have many more genes than simpler ones. Here we are, the most complex and sophisticated animal on the planet, right? You might think that would require a whole lot more genetic information. The betting was on. Just how big would our genome be compared to other life forms? There were estimates that humans would have between, let's say, 80,000 and 120,000 genes. So when the final answer came in 2003, it was a shocker. 23,000 genes. The same number as a chicken. Less than an ear of corn. I mean, people were freaked out by the relatively small number of genes. It's down to something like 22 or 23,000 protein-coding genes in the human genome. The simple nematode worm has about that same number. And there are plants that have considerably more genes than the glorious human genome. The whole Human Genome Project has been a humbling experience, as we've discovered that actually it doesn't take as many genes to make a human as we'd all hoped. And it wasn't just that we had so few genes, but many of our key genes were identical to those of other animals. Huge though the breakthrough had been, the genetic revolution had opened up a whole new set of puzzles. As a solution to the mystery of how evolution works, genes and their mutations were only part of the story. There had to be something else, more subtle and more mysterious going on. We have to explain then, how do you get all these differences, if you have really similar sets of genes? The quest to uncover what Darwin never knew would have to start again. The first tantalizing clues would come from those life forms that Darwin himself had studied. Embryos. Look at these embryos. It is almost impossible to tell just days after conception, which is the chicken, the turtle, the bat, the human. They look almost the same. Only as they grow does it become clear which is which. Darwin wondered, as scientists do today, how could they start out so similar and end up so different? There is something profound about what the embryo is telling us, and we have rediscovered what Darwin was talking about all along, that the embryo is where the action is in terms of animal diversity. It is the platform for diversity. What fascinates modern biologists is that all these different animals don't just look the same. They are using virtually the same set of key genes to build their bodies. The body plan genes determine where the head goes, where the limbs go, and what form they take, whether they are arms, legs, or wings. Another set of genes determines an animal's body patterning, the blotches, the stripes and spots. It is the same genes at work in every creature, from the leopard to the peacock to the fruit fly. And yet they produce radically different results. This has led scientists to a crucial insight about how animal bodies have evolved. It's not the number of genes that counts. It's not the genes you have, but how you use them that generates the great diversity of the animal kingdom. Finding out just how these same genes are used to create such amazing diversity has been the work of Sean Carroll and an unlikely hero of modern science. The Footfly As much as I'd like to study the mammals of the African savannah, they make poor choices for laboratory animals. They're large, expensive, and reproduce very slowly. To get data, we have to find the simplest examples of the phenomenon we want to understand. But the humble fruit fly does weird and wonderful things. This fruit fly is dancing for sex. A rapt female takes in the show. She's particularly besotted by the dark spots on males'wings. Watching it all is an equally besotted Sean Carroll. You might think them just be annoying, but they're really charming. And the males of this species does a rather elaborate courtship dance, where he displays these spotted wings in front of the female. To us, it's as magnificent as what a peacock does. But in some species of fruit fly, the males don't have wing spots. There's another fruit fly species that's different from the spotted species in two important ways. It doesn't have spots on its wings. And it does a lot less dancing. Here then is a classic evolutionary puzzle. Why does one type of fly have spots and the other doesn't? Sean Carroll wanted to know. What is going on in their genes that makes them different? So we wanted to take apart the genetic machinery for making wing spots to understand how those wing spots evolved. Carol began the process of sifting through the two types of flies'DNA. He had one clue to set him on his way. He already knew the gene that codes for the black wing spots. He calls it the paintbrush gene. But surprisingly, when he compared the genes of the two flies, they both had that gene. And yet only one had spots. When we look at that gene in the two species, really, they both have this paintbrush gene. So the big difference is not having the gene, it's how they use it. One species uses it in the wing to make spots, the other one doesn't. So why did the paintbrush gene create spots in one type of fly, but not in the other? In search of answers, Carol turned to one of the least understood regions of DNA, the vast stretches that were once known as junk. It has been called the dark matter of the genome. Mysterious. Uncharted. Strange. The vast bulk of the double helix, some 98% of it, doesn't code for proteins, which make the stuff of our bodies. The genes which do comprise just 2%. Even now, no one is sure what much of this huge non-coding area actually does, but it has long beckoned evolutionary detectives like Sean Carroll. So that's the fragmented test. Yeah. Carol had already learned that the paintbrush gene itself was identical in the two types of fly. So he extended his search through their DNA. And in one place, just outside the paintbrush gene, he found an important clue. A stretch of DNA that was different in the fly with wing spots. What could this mean? So, Carol conducted an experiment. He decided to put that mysterious stretch of DNA that he found in the spotted fly in the unspotted fly. To help him see if it had any effect, he attached it to a gene from a jellyfish, a gene that codes for a protein that makes the jellyfish glow. We cut the DNA up into little pieces and we hook it up to a protein that glows in the dark. And then we inject that into the unspotted fly. And then something remarkable happened. When we looked at those unspotted flies, we see now their wings are glowing in the dark with spots. Somehow that mysterious stretch of DNA had turned on the paintbrush gene in the unspotted fly's wings. Once spotless, now it had luminous spots. Bingo! We'd found the piece of DNA that mattered. Carol had found something that is revolutionizing our understanding of how different animal bodies have evolved. A piece of DNA called a switch. Switches are not genes. They don't make stuff like hair, cartilage, or muscle. But they turn on and off the genes that do. Switches are very powerful parts of DNA because they allow animals to use genes in one place and not another. At one time and not another. And so choreograph the spots and stripes and splotches of animal bodies. In the case of the fruit fly, it's a mutation, a change in just a few letters of the DNA that has caused the paintbrush gene to be switched on. And so a whole new species with wing spots has been created. But switches are now explaining far more than that. They are helping to solve many perplexing evolutionary questions. Like how one creature can become another creature by losing its legs. It all goes back to what Darwin had seen in the snake embryo. The rudiments of leg bumps. This convinced him that a snake must have evolved from some four-legged animal. Over the years, that same mysterious process, the losing of legs, has been seen in other creatures, like the whale. Its front flippers have all the bones of a land creature's arm, even the fingers. And further back in its body. It has the vestiges of a pelvis. Clearly, it is descended from an animal that walked on the land. Lots of animals have evolved to slither through the ground like snakes. Other animals slither or swim through the water like whales. So if you need a streamlined body, it's good to get rid of these things that stick out from the body like limbs. Like the whale, the manatee is another huge mammal that lives in the sea. And it too has lost its hind legs. How? Darwin could never have answered that question. But now, thanks to our understanding of how DNA is switched on and off, and a very small fish, we are getting a little closer. In this lake in British Columbia, there's a creature that really shouldn't be here. A stickleback. Sticklebacks live in the ocean. But some 10,000 years ago, a few were left stranded in this lake, cut off from the Pacific. And over the years, they have evolved. The ocean stickleback has a pair of fins on its belly that are like spikes. They are for defense. The spikes make the stickleback hard to eat. But the lake sticklebacks have lost those spikes on their bellies. And it's this that intrigues researchers David Kingsley and his colleague Dolph Schluter. To understand what's behind it, they first identify the gene that makes the stickleback's spikes. It's one of those key body plan genes, and not surprisingly, they found it to be identical in both the ocean and the lake stickleback. The question was, why hadn't it been turned on in the lake stickleback, which had lost its spikes? Kingsley felt the answer might lie in a switch. We know these genetic switches exist, but they're still very hard to find. We don't have genetic code that lets us read along the DNA sequence and say there's a switch to turn a gene on in a particular place. But eventually, coming through the vast stretch of DNA that does not code for proteins, he found it. A section of DNA that had mutated in the lake's stickleback. These mutations meant that the switch was broken. It didn't turn on the gene that makes spikes. But this work may have implications far beyond sticklebacks. They are convinced that there is a link between the stickleback losing its spikes and other creatures, like a manatee losing their legs. and they have two tantalizing clues. One, the same body plan gene that is responsible for the stickleback spikes also plays a role in the development of the hind limbs. The second clue is more tentative. The lake stickleback may have lost its spikes, but evolution has left behind some tiny remnants. the traces of bones, and they are lopsided, bigger on the left than on the right. We thought, wouldn't it be amazing if in fact this classic unevenness is the signature of using the same gene to control hindlimb loss in an incredibly different animal. So Kingsley and his team went looking in manatees, searching for this lopsided pattern. And they found it. In box after box of manatee skeletons, they saw pelvic bones that were bigger on the left and smaller on the right. Right now, Kingsley and his team were looking for the same switch in the manatee that caused the lake's stickleback to lose its spikes. And if they find it, they will have a powerful explanation for something that baffled Dartmouth. How creatures like manatees, whales, and snakes can evolve away their legs. But all this begs another question. If switches can play such a profound role in the different shapes and patterns of animal bodies, from wing spots to spikes to hind legs, what is throwing those switches in the first place? Researchers would see the answer in animals very familiar to Darwin, those Galapagos finches. Arkat Abjanov and Cliff Taven have spent years trying to find out exactly how those Galapagos finches got their different beaks. Their starting point was what they had learned from Darwin himself. Their beaks were vital to the birds'survival. On an island where the main food was seeds, finches had short, tough beaks for cracking them open. On an island where the main food was from flowers, birds had long, pointy beaks for sucking up nectar and pollen. And they knew something else. The finches are born with their beaks fully formed. So the answer to why they had such different beaks must lie in something that happened to them as embryos in the egg. Something amazing is happening inside those eggs. Genes are turning on and turning off. And depending on exactly how they turn on and off will determine what type of finches form. To find out just what was going on, the researchers first had to collect some eggs. She has two eggs. She's very likely a pest. She has a bunch. Great. She's coming. Abjanov checks a groundfinch nest and finds a single egg. He won't remove it because the mother might abandon the nest. Another nest already has three eggs. He takes one for his research, as he knows the mother will lay a replacement. The team collects several eggs with embryos at different stages of development. That way they will be able to chart exactly how the different beaks grow. Back in the lab, they can begin the process. This cactus finch embryo is well on the way to its signature long pointy beak. And this groundfinch embryo is growing a short, thick beak. What we wanted to do was try and understand the genes that were involved in making the beak the way it was. Making a big, broad, thick beak different from a long, thin beak or a short, thin beak. They concentrated on a group of genes known to control the growth of birds'faces. As they looked, they saw something intriguing. One particular body plant gene became active in the ground finch with the short, thick beak on the fifth day of development. But it didn't go to work in the cactus finch with its long, slender beak for another 24 hours. This was a revelation. The same genes were responsible for the beaks in all types of finch. Any differences were in timing and intensity. We've got it. We nailed it. It's the same genes in making a sharp pointy beak or a big broad nut cracking beak. What's essential, what makes the difference, and all the difference, is how much you turn a gene on, when you turn it on, when you turn it off. And the revelations didn't end there. There was something special about this gene. Like all body plan genes, it doesn't actually make the stuff of our bodies. It didn't make the cartilage for the finches'beaks. It throws switches. And the switches then turn on or off the genes that do make the beak. These are a different type of gene. They're genes that boss other genes around. Scientists now realize that not all genes are created equal. Some make the stuff of our bodies, and switches are needed to turn many of these stuff genes on and off. The body plan genes are what throw these switches, which tell the stuff genes what to do and when. This subtle choreography can have profound effects on how different animal bodies are formed. And this knowledge is helping us solve perhaps the biggest Darwinian puzzle of all, the mystery of the great transformations. It all goes back to Darwin's idea of the tree of life, that all life forms are ultimately related and from the earliest common ancestor over billions of years they have changed and diversified so that creatures that started out looking the same evolved to become completely different. And scientists have made some amazing connections. That dinosaurs share a common ancestor with birds. And that a fish must have been the ancestor of all four-limbed creatures. Even us. Of all his ideas, this was probably Darwin's most astonishing. It was one thing to grasp how two species of finch could become different, how their beak shape could change. That was a small step. But what about the big differences? The differences, say, between the fish that swim in the sea and the animals that walk on land? How did those changes take place? Over the years, evidence for these great transformations has been found. For instance, just a year after Darwin published On the Origin of Species, a fossil called Archaeopteryx was discovered. It had features of both birds and dinosaurs. And Darwin had seen equally persuasive evidence in embryos. Those slits in the ear of all land creatures, even humans. In us, they become tiny bones in the inner ear. But in fish, they become gills. A tantalizing hint that land animals must be descended from fish. But the stumbling block has always been how. How could a fish develop legs and walk on land and how could a fish develop legs and walk on land? Darwin had no idea. But Neil Shubin was determined to tackle that problem. I captured my imagination. I mean, here's a fin, and on the other side was a limb, and they looked different in many ways. And I thought, well, what a first-class scientific problem to devote my research to. And I've been devoting pretty much my research to it ever since, over 20 years. The first stage in Shubin's quest was to find a fossil. If Darwin were right, somewhere out there, there had to be a transitional form. A fossil that was part fish, but had the beginning of legs. But where to look? He had one clue. The fossil record shows that creatures with legs first appeared some 365 million years ago. After that, they were only fish. So summer after summer, Shubin set up camp on Ellesmere Island, just a few hundred miles from the North Pole. It has exposed rock from that crucial transitional time. The scientist's own video shows how remote and bleak the place was. It's cold. It's about freezing every day over the summer. Winds are high. They can get up to 50 miles an hour. There are polar bears there. We have to prepare ourselves by carrying guns. It's a beautiful place. You've got to love it. It's my summer home. Each expedition was costly. But after three of them, there was little to show for their efforts. A fourth trip seemed pointless. I remember having a conversation with my colleagues saying, well, should we go? Is this really a waste of money? This was our do or die moment. And we almost didn't go. But they decided to try one last time. After three days, they still hadn't found anything. Then, just when no one was expecting anything to happen... A colleague was cracking rocks and I was working about five feet from him. Hey, hey guys, what's this? Yes. Sticking out of the cliff was the snout of a fish. And not just any fish, a fish with a flat head. By seeing a flat-headed fish in rocks about 375 million years old, we knew we had found what we were looking for. A flat snout with upward staring eyes. The signature of an animal that pushes its head out of the water. And for that, it would have needed something like arms. What we did at that moment was all jump around, high-fiving. It was a, you know, there were only six of us in the field that time, so it was quite a scene. Back at home, Shubin and his team got to work, examining their 375 million year old fossil. They named their new finding Tiktaalik, an Inuit word for a freshwater fish. Tiktaalik is a perfect transitional form. Much of its body is that of a fish. It's covered in scales. But it also had something very unfish-like. An arm-like fin. Or perhaps a fin-like arm. Tiktallik had the bone structure that is seen in the arms and legs of every four-limbed animal. One big bone at the top, two bones underneath, leading to a cluster of bones in the wrist and ankle. It's the same pattern that is found in everything from sheep to sheepdogs, to Schubin himself. You now have an animal that can push itself up off the substrate, either on the water bottom or on land. One obvious question was why had Tiktaalik evolved this new structure? One possible answer is suggested by other fossils found near it. There are large predatory fish about 10 to 15 feet long living alongside Tiktaalik. Tiktaalik was prey. To survive, it had few choices. You can get big, you can get armor, or you can get out of the way. Shubin thinks Tiktaalik got out of the way. With those arm-like fins, it could have dragged itself to safety on land or in the shallows. But this was only half the answer. What it doesn't show us is the actual genetic mechanism, the genetic recipe that builds a fin into that which builds a limb. At 375 million years old, Tektalik's DNA had vanished long ago. Shubin needed a next of kin. A fish relative that was still alive. What we needed was a creature that was in the right part of the evolutionary tree, but also a fish that has a very fleshy fin. So the search was on. A number of fish fit the bill. But Shubin favored one in particular. The paddlefish. A paddlefish is a really weird fish. They develop this really long snout. And they're really voracious. They eat each other. So oftentimes you'll lose a lot of your fish when they swim together because they'll eat each other. Living in the shallow waters of the Mississippi, it's also a living fossil. Scientists have spent years working out the relationships between different species of fish, and they know that the paddlefish is one of the last survivors of the class to which Tiktaalik once belonged. But unlike Tiktaalik, the paddlefish is in plentiful supply. Paddlefish is a common source for caviar, so we'd get our paddlefish from caviar farms. Intriguingly, even though Tiktaalik is extinct, The paddlefish is actually the more primitive form. Its fins bear far less relation to an arm or leg than tiktalics. And because they are related, the two kinds of fish should share the same genes. So Shubin began looking at paddlefish embryos, hunting for the genes that built its fins. And soon he zeroed in on one particular group of body plan genes, called Hox genes. Hox genes have been found in all complex animals, from the velvet worm that dates back some 600 million years, to the modern human. And in all that time, the letters of their DNA have remained virtually unchanged. They are aristocrats of the gene community, near the very top of the chain of command. They give orders that cascade through a developing embryo, activating entire networks of switches and genes that make the parts of the body. They are absolutely critical to the shape and form of a developing creature. These genes determine where the front and the back of the animal is going to be, the top, the bottom, the left, the right, the inside, the outside, where the eyes are going to be, where the legs are going to be, where the gut's going to be, how many fingers they're going to have. Shubin found that hawk's genes had a key role in the formation of paddlefish fins. One set of Hox genes orders the first stage of fin development, a sturdy piece of cartilage that grows out from the torso. Amazingly, in all four-limbed animals, even us, exactly the same genes create the long upper arm bone. In the paddlefish, another set of hox genes command the next stage of fin development. Again, exactly the same genes control the growth of our two forearm bones. Finally, the same genes working in a different order make the array of bones at the end of the fin. The same sequence of the same genes makes our fingers and toes. This was a massive revelation. Suddenly the origin of creatures with arms and legs didn't seem such a huge leap after all. If the same genes were at work in Tiktaalik, then many of the genes needed to make legs and arms were already being carried around by prehistoric fish. All it needed was a few mutations, a few changes to the timing and order of what was turned off and on. and a fin could become a limb. Oftentimes, the origin of whole new structures in evolution doesn't involve the origin of new genes or whole new genetic recipes. Old genes, old genetic pathways can be reconfigured to make marvelously wonderful new things. So it is now possible to answer what Darwin didn't know and explain how all four-legged creatures could be descended from fish. Around 375 million years ago, a creature like Tiktaalik was under attack. Harried by predators. But some random changes to the activity of the Hox genes led to its fins developing a structure like a limb. Tiktalik could now haul itself out of danger onto dry land. On land, it would have found a world of plants and insects. A world ripe for colonization. A world perfect for animals with arms and legs. And so over millions of years these new limbs evolved, changed and diversified. Some became adapted for running. Others for flying. Some for digging. Others for swinging. And so four-limbed creatures took over the world in a multitude of different ways. And all because of some changes to an ancient set of genes. And this is the true wonder of where our new understanding of DNA has led us to. There are genes that make the stuff of our bodies. Switches that turn them off and on, and still other genes that give those switches orders. Together, in a complex cascade of timing and intensity, they combine to produce the amazing diversity of life on this planet. That, truly, is something that Darwin never knew. But can this new science also explain perhaps the most fundamental question of all? What makes us human? The scope of human activity is simply astounding. What fascinated me were all the crazy things that humans do. You look around the world and if there's something bizarre and interesting that you could be doing, humans are up to it somewhere in the world. And when you look at all of this, you just have to ask yourself, what makes us special? What is the basis for this humanness? For all nature's wonders, the achievements of the human mind are truly unique. We are the only species to think about what others think about us. To punish those who have harmed others. To create art. Music. Architecture. To engage in science. Medicine. The microchip. Only we can destroy millions at the push of a button. Hardly surprising then, that for centuries we thought that humans were different from all other species. Better. Divided in the image of God. But then Darwin began to draw conclusions from evidence like gill slits in human embryos that showed that we were descended from fish. But it was when he drew parallels with other close relatives that he got into real trouble. Shortly after Darwin returned from his voyage, in London, an orangutan named Jenny went on exhibit. And this was a huge sensation. This was the first great ape to be exhibited in captivity. And Darwin was absolutely taken with how she was sort of childlike in her ways. And he saw a lot of human behavior in the way this orangutan behaved. When Darwin suggested that human beings must actually be descended from apes, he was savaged. He was accused of attacking that core belief that humankind had been created in the image of God. above all other creatures. But today, the idea that we share a common ancestor with apes is completely accepted in biology. Instead, as a result of having sequenced the genomes of both humans and apes, we face a very different puzzle. Katie Pollard is an expert on chimp DNA. Given all the obvious differences between humans and chimps, you might expect our DNA to be really different. But in fact, it's more like 99% identical. Just a 1% difference in the DNA of humans and chimps. The mystery facing modern science is not how can such different animals be related, but how can such closely related species be so different? That really is something that Darwin never knew. But slowly, scientists are starting to find the answers. And one answer begins with insights into the genetics of a key human organ, our hands. The human hand is a marvel. Nimble and dexterous, nothing quite like it exists anywhere else in nature. It offers us a unique combination of precision and power. And much of that is down to one particular digit. Our thumb. One of the features of the human hand is our ability to touch all four fingers with the thumb. And that allows us to make grips like this. It gives us a lot of precision. The power grip is the ability to put a lot of strength into this sort of contact. So if you're holding a ball, you're basically pinching it. And we can put a lot of strength into that. the better to throw a fastball with. Finding out why we have such versatile hands compared to our nearest relatives is the task of Jim Noonan at Yale University. He began sifting through that vital 1% of DNA that is different in humans from chimps. It's kind of one of the fundamental questions in science, is what makes us who we are. That's really what we're trying to get to. What makes humans human? It was slow work. One percent may not sound like much, but it's still some 30 million of DNA's chemical letters. A's, T's, C's, and G's. The genome's a big place. And just by looking at sequence you really can't tell for the most part what is important and what isn't. But eventually in human DNA he spotted something. A sequence that was different in 13 places compared to chimp DNA. The trouble was, he had no idea what this piece of DNA actually did. To find out, he inserted it into the embryo of a mouse. To make the effects of the DNA easier to follow, he attached it to another gene that gives off a blue color. That way he could see where the gene became active in the embryo. As the embryo developed, the piece of DNA seemed to be active all over the place. But most intriguingly, it was doing something in the growing paw. Well, I thought, wow, this is really cool. It was a really, really striking image. What Noonan saw was that the human DNA became active in the mouse embryo's thumb and big toe. It seems that Noonan may have found a switch that helps form that key human attribute. Our thumb. The part of our hand that gives us so much power and precision. It's that power and precision that enables us to hold a paintbrush. Manipulate tools. pilot a jet fighter, record our thoughts, all those things that separate us from other apes. Of course having a nimble hand is one thing, but you have to know how to use it. And for that, you need to have humankind's other signature organ. Our brain. The human brain is vast, three times bigger than a chimp's, and is structured very differently. How this extraordinary organ evolved is central to understanding why we are the way we are. It is something that Darwin himself was at a loss to explain, which is why many of his critics remained unconvinced by his account of human origins. But now, part of the answer to why we have such a remarkable brain may have come from a surprising source. Hansel Stedman is a dedicated athlete and a medical doctor. He never imagined he would come up with an answer to a profound evolutionary mystery. He has devoted his career to trying to cure muscular dystrophy, a distressing and sometimes fatal degenerative disease. His quest is very personal. My first exposure to muscular dystrophy was inescapable. My younger and my older brother, both born with muscular dystrophy. Muscular dystrophy is a genetic disease. Its sufferers have a mutation in one gene that robs their muscles of the ability to repair themselves. Typical workout here on the rocks might blow through a few thousand muscle cells, but they'll regenerate overnight and, if anything, be a little stronger the next day I come in. as a result of all of that. Whereas in muscular dystrophy the injury process is greatly accelerated and the injury process outstrips the body's ability to repair. In search of a cure Stedman is investigating the hundreds of genes that control the development of muscles. So when the Human Genome Project took off Stedman seized his chance. When the horsepower of the entire Human Genome Project kicked in, we knew exactly what to look for. Stedman was hunting for any new muscle-making genes. And so, as the human genome was sequenced, he began sifting through the vast mountains of data. Eventually, he found what he was looking for. A previously unidentified muscle-making gene. But there was something strange about this new gene. It didn't look like any other muscle-making genes. Two letters were missing. This gene should cause a disease. It became very clear early on that if you have a mutation of this type, you get some serious muscle problem going on. Here was a puzzle. Why would humans carry a gene that was clearly damaged? Perhaps it was simply a mistake in the data. Stedman decided to dig a little deeper and look in another human subject. In the Department of True Confessions, we do certain experiments first on ourself, largely out of convenience. You know, you can swab your own cheek and get working on some DNA. To his utter amazement, he found the same damaged gene in himself. I'm seeing this in my own DNA and it's suggesting, now wait a minute, that means there's a muscle disease here somewhere. A muscle disease that I'm unaware of and I thought it would be worth checking this out in some other members of the lab. A few swabs later and... Sure enough, at the end of the day, every single person had the same glitch in their same DNA at the same place. Here, then, was a real mystery. It seemed that this particular muscle-making gene was common in humans. But when he identified the same gene in apes, it was just like any other muscle-making gene. Why was there such a difference? What did this gene enable one species to do that the other could not? Stedman began to research the role of this gene in apes, and he found it made one particular kind of muscle. The muscle for chewing. In fact, the muscle used to close the jaw. In humans, that genetic glitch meant that we chew with just a fraction of the force of an ape. This in itself was interesting, but where Stedman went next was truly intriguing and highly controversial. He drew a direct connection between the power of our jaw muscle and the evolution of the human brain. Stedman's thinking goes like this. The skulls of apes and humans are made of several independent bone plates. They let our heads get bigger as we grow. The muscles for chewing pull against these plates. And in an ape, these forces can be enormous. In the gorilla, the muscle, the size of a human thigh muscle, lives here and has to go through this large space. to power the jaw moving back and forth. We're not talking biceps, tricep, we're talking quad here. This is an enormous muscle that has to come right through this hole here to power the jaw-closing apparatus. Stedman contends that all this muscle power forces an ape's skull plates to fuse together at an early stage. And this puts limits on how much the brain can grow. In the chimpanzee, gorilla, orangutan, those growth plates are pretty much shut down, closed for business by about three, four years of age. In a human, they remain open for growth to perhaps age 30. This, Stedman believes, is the key. A mutation in our jaw muscle allows the human skull to keep expanding into adulthood, creating a bigger space for our brain. And so our most important organ is able to grow. It's very cool to us to think that some kind of muscle altering mutation might have actually been a signature event in the evolution of what makes us distinct as a species. It might have been an absolute prerequisite for us landing where we are today. But having the space for a big brain is one thing. What is needed to actually grow one? That is the question that Chris Walsh is trying to answer. He's another scientist who never expected to be taking on what even Darwin didn't know. I never thought that I'd be studying evolution. I'm a neurologist interested in the brain and in kids with neurological problems. How you doing buddy? You doing alright? Huh? Doing okay? No one was more surprised than us to find that the study of kids with disabilities would lead us into these fascinating evolutionary questions. Is breathing generally okay during the day? Sometimes when he gets startled, it'll go up fast, like, but then he calms himself right back down and it calms back down. Walsh is a specialist in a rare disorder called microcephaly. Children with microcephaly are born with brains that can be half the normal size. This disorder can be very devastating for the kids that have it. They typically will have severe mental retardation, and so will not be able to achieve normal language and normal schooling. And so it's really an event that defines the whole family. It defines the lives not only of the child, but of the parents of that child. And these families are desperately eager to try to understand at least what caused the disorder in their kids. The purpose of Walsh's work was initially to help families that might be carrying any defective genes causing microcephaly to plan their lives. We're able to offer those families predictive testing so that if they're planning on having additional children, we can tell them ahead of time whether that child is likely to be affected or not. First, Walsh had to decide where to look in the vast genome to find any possible microcephaly-causing genes. So he focused on one particular area of DNA. Other research suggested it contained a gene involved in the condition. That gene is known to control how and when brain cells divide in animals, such as fruit flies and mice. What this gene seems to do is help control the fundamental decision that the brain has to make, which is, when do I stop making cells? When is the brain big enough? Then his team began searching for that same gene in a family with a history of the disease. And sure enough, they found something. A gene that helps direct brain growth. And crucially, it was defective. Walsh decided to check this finding in other patients. Once we found this gene, we sequenced it in our kids with the microcephaly disorder, and we found that one family after another had a disabling change in the gene that completely removed its function. In total, he has found some 21 different mutations responsible for microcephaly. Sometimes one of the DNA's chemical letters is replaced with another letter. Sometimes letters are missing entirely. But whatever the defect is, they all stop the brain cells from dividing at a very early stage of development. Walsh was now certain, thanks to his microcephaly patients, he had found a gene key to the growth of the human brain. Now he decided to compare normal versions of the gene found in healthy humans with the same gene in chimpanzees, our closest relatives. And what he found was astonishing. The gene in humans was radically different from that found in chimps. There had been a large series of mutations. It could be that these mutations were a major factor in the evolution of our huge brains. And this discovery came about only because of Walsh's work with his patients. I think one of the amazing things for us was the extent to which studying human disease can unexpectedly enlighten us about something like human evolution. But this is only the beginning of our understanding of the evolution of the human brain. It's an area of research that is now attracting scientists with a range of skills that Darwin would have marveled at. Katie Pollard is a biostatistician. Her life is spent crunching numbers. What I love about my work is geeking out on a computer and writing programs and thinking about biology. And that in doing this, I'm actually working on something that not just scientists care about, but really every human being can relate to and cares profoundly about. And that's what makes us human. Pollard has constructed an ambitious computer program. It's designed to highlight DNA that is similar in apes and other animals. but which is very different in humans. That way, she hopes to identify the key DNA that makes us, us. Out of these 15 million letters that make humans different from chimps, we need to try to figure out which ones were important. And so we use a technique which is to look for places where human is different from chimp, but chimp looks almost identical to the other animals. She too is looking for DNA relating to the human brain. The brain is one of the things that's changed the most during human evolution, both in terms of its complexity and its size. And so when we look to find the parts of our genome that make us human, we're particularly interested in finding out whether these are things that are involved in the brain. It is a huge feat of number crunching. As Pollard loaded in DNA sequences from both humans and chimps... You basically take a bunch of computer hard drives and you stack them up together. We were able to take a task that would have run for 35 years on a desktop computer and do it in one afternoon. And at the end of that afternoon, they had a whole array of material charting the differences between humans and chimps. Importantly, many of those differences were not in the actual genes. They were in switches. It turns out that the vast majority are not genes. Instead, they're pieces of our DNA that we can think of as switches. They're pieces of DNA that turn a nearby gene on or off. that tell it where, in what cells in our body, in what tissue, at what time, or at what level to be operating. And there was something even more intriguing about those switches. A large number of them, more than half, were nearby a gene that was involved in the brain. In Pollard's work, one particular piece of DNA stood out. It was a piece of DNA that is known to be active in the development of one of the key parts of the human brain in the embryo, the cortex. The cortex is that wrinkled outer layer of our brain. It's vital for those defining human capabilities like language, music, and mathematics. When she looked at that DNA in chimps and compared it to the same DNA in a chicken, it was different in just two letters. But in humans, it was different by 18 letters. A massive mutation. This was about as great of a eureka moment as you could have as a scientist. So here is another intriguing piece of evidence suggesting how DNA can shape our distinctive human qualities. We now know that DNA works in many different ways. Through genes that make the stuff of our bodies, through switches that turn those genes on and off, and through sequences of DNA's chemicals that throw those switches. Taken together, what this all adds up to is a way that we can at last understand how small differences in DNA can generate enormous change. Basically, you can make massive changes just changing those switches. So a small change, a couple of DNA letters, could have a profound effect. And so that final Darwinian puzzle. How a human can be so closely related to an ape, and yet be so different, is now, slowly, being answered. 150 years after Darwin first put forward his grand theory to explain the great diversity of life, The scientists who carry on his legacy have advanced his work in wondrous ways. I think if Darwin were here today, he'd be absolutely stunned, delighted, even moved to see how much his theory has grown. What we now are able to understand on the one hand would just blow him away, but I also think it would give him enormous satisfaction because ultimately everything we've been learning validates the things that he said. I think that Darwin was a remarkable scientist and absolutely should be celebrated. However, I do not think that he was the... end of evolution. On the contrary, I think he was the beginning. He outlined the major points, but we have discovered more than I think he would have imagined possible. As we celebrate the 200th birthday of Charles Darwin and the 150th anniversary of his great work, there is still much more to understand about how the endless forms of nature have arisen. And in rising to that challenge, it is likely to continue to advance medicine and come to a better understanding of ourselves as well. Thank you.