I<\/span>n the collection of the Peabody Museum at Harvard University reside the mummified remains of a very peculiar creature. It has the shrunken head, torso and arms of a monkey, but from the waist down, it is a fish. This bizarre hybrid was bought by Moses Kimball, founder of the Boston Museum, from the family of a sea captain. Kimball leased it in 1842 to the impresario P. T. Barnum for his popular American Museum in New York City. Barnum claimed it was a mermaid found in Fiji.<\/p>\n In fact, such artifacts, typically intended for sale, were made from animal parts by fishermen and artisans in Japan at the time (although some of the mermaid seems to be fashioned from papier-m\u00e2ch\u00e9). Mythical hybrid beasts such as mermaids, centaurs and chimeras testify to our enduring fascination with the plasticity of biological form: the idea that natural organisms can mutate or be reconfigured. Both in legends and in fiction, from H. G. Wells’s 1896 novel The Island of Doctor Moreau<\/em> to the 2009 movie Splice<\/em>, we seem inclined to imagine living organisms as assemblies of parts that can be shuffled and rearranged at will.<\/p>\n But a crude stitching of components will not produce a viable organism. Bodies aren’t a collection of arbitrary pieces; a human embryo grows into a being with the standard features of a human body, all the parts working in synchrony. Biological forms seem to have inevitable, unique target structures.<\/p>\n An emerging discipline called synthetic morphology is now questioning that notion. It asks how, and how far, the natural shapes and compositions of living matter can be altered. The goal is not to create grotesque creatures such as the Fiji Mermaid but to understand more about the rules of natural morphogenesis (the development of biological form) and to make useful structures and devices by engineering living tissue for applications in medicine, robotics, and beyond.<\/p>\n Synthetic morphology might be considered the next stage of synthetic biology. The latter discipline has racked up impressive achievements in retooling cells for nonnatural tasks\u2014for example, programming bacteria to glow in the presence of pollutants and other chemicals. Much of synthetic biology involves genetic engineering to introduce networks of genes that give cells new functions, such as manufacturing enzymes to make a nonnatural molecule.<\/p>\n Synthetic morphology works at the next level: controlling the shapes and forms into which many cells will assemble. Using the cells of multicellular organisms (like us), the technology might allow scientists to design entirely new tissues, organs, bodies and even organisms by exploiting the tremendous versatility and plasticity of form and function that seem to reside in living matter. The possibilities are limited only by our imagination, says bioengineer Roger D. Kamm of the Massachusetts Institute of Technology. We might design a novel organ, for instance, that secretes a particular biomolecule to treat a disease, similar to the way the pancreas secretes insulin. It could have sensor cells that monitor markers of the disease in the bloodstream, akin to controlled-release implants already used to administer drugs\u2014but alive. Or, Kamm says, we could make \u201csuperorgans\u201d such as eyes able to register ultraviolet light outside the visible spectrum.<\/p>\n Ultimately we can imagine creating entirely new living beings\u2014ones shaped not by evolution but by our own designs. \u201cBy studying natural organisms, we are just exploring a tiny corner of the option space of all possible beings,\u201d says biologist Michael Levin of Tufts University. \u201cNow we have the opportunity to really explore this space.\u201d Synthetic morphology poses deep questions that challenge the status quo in biology: Where does form come from? What rules has evolution developed for controlling it? And what happens when we bypass them? Doing so could turn on their heads our traditional notions of body, self and species\u2014even of life itself.<\/p>\n Thinking of living matter as a substance that can be shaped and engineered at will was a revolutionary idea that arose in the 19th century. Zoologists had long regarded biological forms as innate, and Charles Darwin argued that natural selection sculpts them to be adapted to their environment. In the mid-1800s others, such as Darwin’s supporter Thomas Henry Huxley, began to suspect that there was a generic form of \u201cliving matter\u201d\u2014often called protoplasm\u2014from which the most primitive life-forms were fashioned.<\/p>\n In his 1912 book The Mechanistic Conception of Life<\/em>, German physiologist Jacques Loeb argued that life could and should be understood according to engineering principles. After discovering that he could stimulate asexual reproduction by treating unfertilized sea urchin eggs with simple salt solutions, he became convinced that nature’s way of doing things with living matter is not the only way. \u201cThe idea is now hovering before me,\u201d he wrote, \u201cthat man himself can act as a creator, even in living nature, forming it eventually according to his will.\u201d<\/p>\n Around the same time Loeb’s book was published, French physician Alexis Carrel developed techniques for growing tissues in a culture medium: a kind of unformed living material. He hoped it might become possible not just to preserve but to grow organs outside the body for transplantation when the natural ones wear out, thereby conveying the prospect of immortality.<\/p>\n That hasn’t happened, but tissue culture is now a well-established technology used to make, for instance, synthetic skin for grafts. It is now routine to cultivate living cells, including those of human tissues, in a petri dish, sustaining them with the nutrients they need to metabolize, replicate and thrive\u2014much as we can grow colonies of bacteria or yeast.<\/p>\n The idea of cells as the \u201cbuilding blocks\u201d of our bodies might make them seem rather passive, like mere bricks to be stacked in the masonry of tissues. But they are much smarter than that. Each cell is in many respects a living entity in its own right, able to reproduce, make decisions, and respond and adapt to its environment. Multicellular living matter concocts its own schemes, which means cells won’t necessarily stay in the same place or state.<\/p>\n This is strikingly apparent in the development of a new organism\u2014a human being, say\u2014from a single fertilized egg, or zygote. As that single cell becomes two, four and eventually many billions, it changes from what looks like an unstructured ball of identical cells to a body with a well-defined shape containing distinct tissues in which cells carry out different roles\u2014producing the electrically coordinated contractions of the heart, for example, or secreting the hormone insulin in the pancreas.<\/p>\n Scientists and natural philosophers have wondered for millennia where this body plan comes from. How does the featureless blob that is the early embryo know what to make and where to make it? The answer, according to biology textbooks, is that the plan is contained in the cells’ DNA, encoded by genes. But this notion quickly falls apart. Yes, all the zygote seems to get by way of instruction is a genome, but you will look there in vain for any blueprint for a heart or brain. The genes simply encode proteins or other molecules that can ramp their production up or down.<\/p>\n It’s better to think of the molecular networks of the cell as encoding certain behaviors and tendencies, from which morphology emerges when those impulses play out among many cells. To understand\u2014and perhaps ultimately to control\u2014the forms of multicellular structures, we need to figure out these behavioral rules.<\/p>\n Cells produce order and form by communicating with and responding to one another. Each is bounded by a membrane studded with molecules, generally proteins. These molecules are capable of receiving signals at the cell surface and converting them into messages within the cell’s internal networks, typically ending with the activation or suppression of specific genes.<\/p>\n There are three main modes of communication for these externally derived signals. One is chemical: a molecule arrives at the cell surface and binds to a protein receptor there, triggering some change in the receptor that initiates a signaling cascade in the cell’s interior.<\/p>\n
Alternatively, activity within a cell can be altered by mechanical signals such as stretching of the membrane when another cell sticks to and pulls it. Typically these mechanical signals are \u201ctransduced\u201d\u2014converted to some internal effect\u2014by membrane proteins that alter their behavior when pulled or squeezed, to admit or exclude, for instance, electrically charged ions attempting to enter the cell.<\/p>\n The third mode is directly electrical. Ions passing across a cell’s membrane can make the cell electrically polarized. That’s how electrical signals are transmitted through heart muscle to induce regular contractions: the pulses travel from cell to cell via connections called gap junctions. Such electrical signaling is a capability shared by most cells.<\/p>\n Levin thinks bioelectric signaling between cells creates particularly powerful information-processing capabilities that can influence morphology. It therefore represents a useful \u201ccontrol knob\u201d for applications in regenerative medicine and synthetic morphology, he says. Levin, Vaibhav Pai of Tufts and their colleagues have shown that the development of neural structures in the frog brain seems to be governed by the voltage across the membranes of embryonic cells<\/a>. When the researchers permanently activated a key gene called Notch<\/em> (one of the factors that induces precursor cells to become neurons in frog embryos), brain development was disrupted. But they were able to put it back on the right track by changing the membrane voltage of other cells nearby: the bioelectrical signal overrode the message coming from the genes, allowing proper morphogenesis to proceed.<\/p>\n Morphogenesis is a subtle process involving the interplay of information at the scales of the whole organism, the genetic and molecular activity in its cells, and everything in between\u2014a complex mixture of bottom-up, top-down and middle-out signaling. If cells multiply faster in one part of the embryo than another, the developing tissue may buckle and fold. This deformation creates mechanical stresses that feed back into those cells to switch certain genes on and off, differentiating the cells from others around them and directing them along a developmental trajectory toward a particular tissue or organ.<\/p>\n In another example, as a mass of cells grows in a fetus, those in the interior might get cut off from the oxygen-ferrying blood pulsing down capillaries, triggering them to produce and release chemicals that induce some of their neighbors to develop into blood-vessel-forming cells. There was never any blueprint for a vascular system in the cells’ DNA; rather the eventual network of branching tubes is an emergent morphology produced by the rules of cell interaction and response.<\/p>\n \u201cThe genome specifies a cellular collective with massive plasticity,\u201d Levin says, \u201cwhich executes rearrangements until the correct target morphology is achieved.\u201d One of the most striking illustrations of the existence of such target forms is the way a tube called the pronephric duct, a precursor to the kidney, grows in newts. If cells had genetic instructions telling them to assemble into a tube, we would expect bigger cells to make a proportionately bigger tube. In the 1940s, however, embryologist Gerhard Fankhauser tested this idea by using cells with extra chromosomes that made them grow larger than their usual size. He found that a tube of normal diameter and thickness developed\u2014it just contained fewer cells. The largest cells changed shape to make the structure almost on their own. It was as if the cells collectively \u201cknew\u201d what their target structure was and adjusted their individual behavior accordingly. Albert Einstein was fascinated by these experiments, writing to Fankhauser that \u201cwhat the real determinant of form and organization is seems quite obscure.\u201d<\/p>\n An even more striking example of this apparent \u201coverall vision\u201d of multicellular structures is found in primitive flatworms called planarians. Cut a chunk out of a planarian, and it will regrow exactly those tissues that were removed, neither more nor less. Even a small part of a planarian can regenerate into a full worm with the typical shape and proportions. This capacity is all too evidently lacking in humans\u2014so how do planarians do it? It seems to entail an ability of the regenerating cells to \u201cread\u201d the overall body plan: to take a peek at the whole, ask what’s missing and adapt accordingly to preserve morphological integrity. They are able to make use of top-down information. Levin believes this information is delivered to the cells via bioelectric signaling, which governs the maintenance of form in other organisms such as fish, frogs and humans. When he and his colleagues manipulated pieces of planarians to alter their bioelectric state, the regenerating cells produced unexpected anatomies\u2014for example, worms with a head at each end.<\/p>\n Such regenerative potential is available to amphibians such as axolotls and salamanders, which can regrow limbs and tails that have been amputated. That feat demands two morphological capacities: the regrowing cells must be able to develop into many tissue types, such as skin, muscle, bone and blood vessel, and those tissues have to spontaneously organize themselves in the right way. Amphibians keep a reserve of such versatile cells, called stem cells, for repair jobs. If we are to find ways of imbuing our own bodies with regenerative powers, we need to know and master the global rules governing form.<\/p>\n All embryos contain a ball of cells that are able to develop into any of the body’s tissue types, a property called pluripotency. In humans, however, these cells gradually lose this plasticity through a succession of transformations that differentiate them into specialized roles. It was long assumed that when these embryonic cells lose their pluripotency, that versatility is gone forever. But in 2006 biologist Shinya Yamanaka of the University of California, San Francisco, and his co-workers showed that this isn’t so. They were able to switch mature, differentiated mammalian cells back into a stem-cell-like state by injecting them with a cocktail of the genes that are active in embryonic stem cells (ESCs), essentially rewinding the clock of embryo development. Their experiment demonstrates that the fates of our cells, and the nature of our tissues and bodies, are far less inevitable and inexorable than people had thought: living matter is plastic and programmable.<\/p>\n
Cell reprogramming is now being explored for regenerative medicine. Some researchers are seeking to combat macular degeneration, a common cause of blindness, by reprogramming cells in the eye<\/a> to support light-sensitive retinal cells. Others hope to cure neurodegenerative diseases such as Parkinson’s or spinal injuries by using neurons made from induced pluripotent stem cells (iPSCs) that can restore damaged connections in the nerve networks.<\/p>\n When cells are reprogrammed, they also acquire new morphological knowhow. For example, skin cells reprogrammed into iPSCs that are then cultured as neurons in a petri dish might not simply grow into a tangled mass. In the right growth medium, they might instead try to become a brain, recapitulating some of the structures seen in developing brains, with organized layers of cortexlike neurons and some of the characteristic folds seen in a mature cortex.<\/p>\n Such reprogrammed cells are not terribly good at making whole organs because they are missing some important information that, in an embryo, would come from the surrounding tissues. And currently such \u201corganoids\u201d can’t grow very large because they lack a vascular network<\/a>, meaning the cells in the center eventually become starved of nutrients. To solve that problem, researchers are looking for ways to encourage some of the cells to develop into blood vessels. If transplanted into mice, liver organoids will spontaneously integrate with the animal’s own blood supply.<\/p>\n Another demonstration of the versatility of cells in multicellular structures is provided by so-called chimeric embryos, which contain cells from more than one type of organism. Because very different species usually can’t interbreed, monstrous hybrids such as the Chimera of Greek mythology seemed biologically implausible; the only way to make something like the Fiji Mermaid was to crudely stitch together lifeless carcasses. But at the level of individual cells, the species barrier isn’t as important as we might think. All cells speak much the same language, and those of different species seem to get along fairly well in an embryo. Scientists have created several chimeric animals\u2014mosaics of cells of different species, such as the goat-sheep blend called a geep\u2014by adding stem cells from one species to the embryo of another.<\/p>\nThe Rules of Living Form<\/h2>\n
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\n<\/figure>\nThe Plasticity of Cells<\/h2>\n
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