IT STARTS with a single cell. From this cell can come a dizzying variety of shapes and forms, from trees to jellyfish to people. We take this process so much for granted that we forget how extraordinary it is.
So how do organisms assume their forms? One answer is that it is written in their DNA. By studying bizarre mutants such as flies with legs in place of antennae, we have identified many of the genes involved in development.
The reality, though, is that we are like a bunch of kids who have got their hands on an alien spacecraft and managed to work out roughly what the switches do by playing with them. We might be able to make it move, but we don’t have a clue how it works – and we certainly couldn’t fix it if it went wrong, or build another spacecraft from scratch.
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Similarly, although we know a lot about which genes direct growth, we know far less about how those instructions lead to a final shape. What cells and molecules are actually doing to transform an organism’s contours is still a tremendous mystery – perhaps the biggest in biology.
But with the help of new tools, we are starting to make inroads. And the possibilities of this work are endless. The more we understand about how organs form, the easier it will be to repair or replace them, for instance. Ultimately we may be able to create plants and animals with shapes unlike anything found in nature.
Although thinkers like Aristotle have pondered the mystery of development since ancient times, biologists only started to get to grips with it in the second half of the last century. In the 1960s, biologist Lewis Wolpert set out how complex body plans could be established by simple gradients in the concentration of chemicals across embryos. Different genes get activated in different places depending on the local level of these compounds, called morphogens.
His ideas were largely confirmed in the next few decades, with the discovery of genes that encode morphogens. By tinkering with the genes that control body plans, biologists discovered how to transmogrify a flower’s pollen-bearing organ into a petal, for instance.
But the emphasis was on cataloguing the “master” genes involved in development, rather than elucidating how it proceeds, step by step. In most cases no one knew what happened after these master genes switched on the program for making a specific body part. “Biologists got obsessed with genes and basically stopped even noticing that there was a question in terms of shape,” says James Sharpe, a systems biologist at the Centre for Genomic Regulation in Barcelona, Spain.
“Biologists got obsessed with genes and stopped even noticing there was a question in terms of shape”
Take animals’ limbs. The first step in growing a limb, be it a chicken’s wing or a mole’s paddle, is the formation of an elongated appendage. For years, biologists assumed that this shape came about simply because cells divide more quickly at the limb’s tip than at its base, but no one had proved it.
Out on a limb
Sharpe’s team recently tested the idea by capturing 3D images of a mouse’s growing limb and measuring how quickly cells divided along it. When they fed the data into a computer model, they found there was no way that differences in rates of cell division could explain the limb’s shape. Cells at the tip divided only about twice as fast as the ones near the body. In the model, this made the virtual limb puff out like a balloon rather than elongate ().
Instead, Sharpe thinks cells might actively move in a specific direction to form the limb. It has long been known that cell movement plays a major role in the development of animals, and his team noticed that chick limb cells have long protrusions called filopodia, which can help cells crawl. The filopodia are generally aligned in the direction of the nearest outer layer of tissue, which, away from the tip, can position them at near right angles to the long axis of the limb. If the cells migrated in this direction, they would push some of their neighbours outwards as they squeezed between cells.
Although limb formation remains a puzzle, the past decade has seen a lot of progress in understanding plant growth. The growth of a leaf, for example, is triggered by high levels of a morphogen – in this case a plant hormone, or auxin. But what makes levels high in the right places? The first clues came from mutant plants with a naked, pin-like stem. These mutants lack a protein called PIN1, which actively pumps auxin out of cells.
In a 2003 study, Cris Kuhlemeier at the University of Bern in Switzerland and colleagues added fluorescent labels to the PIN1 proteins in thale cress. They found that the proteins clustered in spots at the ends of cells closest to sites where leaves later emerged (). This suggested that the PIN1 molecules were pumping auxin toward places where leaves should grow.
How do cells know where leaves should form? They don’t, the team suggested. Instead, the PIN1 transporter proteins act like metal filings attracted to a magnet – in this case, auxin – that draws them to one side of the cell. The upshot is that each cell follows a very simple rule: pump auxin towards the neighbouring cell that has the most auxin. This produces a peak in auxin levels in one spot, triggering formation of a leaf.
As the stem continues to grow, auxin gets depleted in some cells, with the result that some cells far from the developing leaf end up with more auxin than their neighbours. The surrounding cells then switch to pumping more auxin in this direction, leading to a new peak in auxin levels and a new leaf. In 2006, could generate virtual plants with perfectly ordered leaf arrangements. Tweaking the model’s parameters produced different arrangements just like those seen in different plants.
Similar principles govern the shapes of leaves, such as how they develop a serrated edge. Miltos Tsiantis, a developmental geneticist at the University of Oxford, UK, and his colleagues have shown that protrusions in thale cress leaves form where auxin levels peak, while indentations form at the peaks of another molecule thought to suppress growth. show that simple feedback loops, involving the funneling of auxin by PIN1, can produce alternating peaks of auxin and the growth suppressor along the margin of a leaf, and thus a serrated shape.
A sense of direction
All these studies suggest that polarity – the idea that each cell has a sense of direction – is key to forming shape. “You might think, oh, it doesn’t know one end from another,” says Enrico Coen, a plant developmental biologist at the John Innes Centre in Norwich, UK. “But actually cells do have orientation.” He compares the phenomenon to a crowd of people in a sports stadium, where everyone faces the action.
This sense of direction also helps to explain the many leaf shapes seen in nature. In a study published earlier this year, Coen’s team looked through a microscope at the position of fluorescently labelled cells in thale cress leaves to see how the tissue grew. Then they devised a computer model to try to account for those changes. The team was able to reproduce the observed growth patterns using a model in which the tissue had a sense of which direction to grow in, and the ability to grow at varying rates. Tweaking the model’s parameters – for example, changing levels of a protein – generated an array of leaf shapes similar to natural ones, including ovals and hearts ().
In addition to cells having a sense of direction, it is also clear that the physical forces on developing organs play a big role in shaping them. “At some point, mechanics has to be involved,” says Olivier Hamant, a plant biologist at the French National Institute for Agricultural Research, who is based in Lyon.
In 2008, his team showed that plant cells rearrange some of their contents in response to physical forces. When the researchers squeezed the tip of a stem between two Teflon blades, protein fibres called microtubules in the cells lined up parallel to the blades (). Those microtubules prompt the cell to reinforce nearby sections of its wall, making it harder for the cell to expand towards the blades.
This restricted growth could also explain how plants grow cylindrical stems. The cells on the surface of the stem are constantly being pushed outward by cells further in, and may strengthen parts of their walls to resist those forces. This may also cause the outer cells to grow more in the direction of wall segments that have not been reinforced, pushing the tissue into a vertically elongated shape. Hamant’s team found that a model implementing those rules could produce a vertical cylinder, just like a natural plant stem.
Physical forces could also give plant cells their sense of direction. Take the example of auxin and its transporter, PIN1. The theory is that somehow each cell knows which neighbouring cell has the most auxin, and that PIN1 molecules inside each cell move to the end nearest that cell. But the mechanics behind this process are unclear.
One possibility is that the cell is responding to physical stress. If a cell contains a lot of auxin, its wall loosens and the cell expands, stretching the wall it shares with its neighbour. That neighbour might respond by sending PIN1 molecules toward the source of this mechanical stress. A recent study found that, like microtubules, PIN1 proteins line up parallel to the direction of mechanical stress on a cell ().
We still have a long way to go before we fully understand the mysteries of shape. Yet with plant biologists now creating simple computer models of how structures develop, we are beginning to be able to predict how certain changes will affect their shape. In theory at least, such models could one day help us to design plants with specific shapes.
Of course, breeders have influenced the shapes of crop plants, flowers, fish, dogs, horses and many other organisms for millennia. If they wanted a short-legged dog, for instance, they mated two dogs with short legs. But most of this work was done blindly, without knowing the underlying mechanisms. Understanding how the interplay between genes, morphogens and physical forces affects shape will open up many new possibilities.
Our growing understanding of the role of physical forces is already helping improve tissue engineering. By understanding how cells respond to stresses, researchers can grow better replacement tissues in the lab and speed up wound healing in patients. For example, artificial cartilage becomes stronger if squeezed regularly, the same way it would be when a person walks.
As biologists get to grips with more of the details behind form, it is tempting to imagine that a wild and wonderful world of new shapes could be created. Plants can already be coaxed to form all kinds of extraordinary shapes. People have made tomatoes square by enclosing the growing fruit in little boxes, trained trees to assume shapes like chairs and even created living bridges from tree roots. But what if the instructions for such shapes could be genetically encoded in seeds, ready to spring up when planted? Could we engineer watermelons with handles for carrying, daisies with flowers like exotic orchids or trees that grow into ready-made houses?
“It is tempting to imagine that a wild and wonderful world of new shapes could be created”
The chickenosaurus
We are nowhere near this stage yet, but we are taking the first baby steps. In a recent study, for instance, Andrew Fleming at the University of Sheffield, UK, and colleagues genetically engineered cress in a way that allowed them to suppress growth in places. They were able to change the plants’ form in predictable ways, such as making leaves buckle into a bowl shape rather than remaining flat ().
Animals are a far greater challenge. But genetically modified pets, such as fluorescent “GloFish”, are already on sale, and a few biologists are dreaming of far more exotic creations. One idea is to create a “chickenosaurus” – tweaking chicken’s genes to give them the form of their dinosaur ancestors, the maniraptors. What child wouldn’t want their very own pet dinosaur?
Of course, there are ethical concerns. Attempts to create new shapes by modifying genomes could produce sickly creatures. Traditional breeding has already done this: , such as bulldogs that can barely breathe.
There are also limits to what can be done. It might one day be possible to engineer horses to grow wings, for instance, but there is no way such creatures will ever fly. They probably wouldn’t be much good at running either. But evolution has produced many fantastical forms, from birds of paradise to stick insects to the blue whale, and ingenious designers should eventually be able to outdo nature.
Many researchers, though, are driven by the desire to understand growth, rather than by the prospect of engineering new forms. Fleming likes to quote the Austrian writer Hugo von Hofmannsthal, who wrote in 1898: “If I knew how a leaf from a branch grew precisely, forever silent would I remain, for my knowledge would suffice.” More than a century on, we are still not quite there, but we are getting closer.
