by Frank Stephenson

    From the simplest, one-celled animals to the greatest beasts ever to trod Earth or swim its seas, perfecting the machinery of movement has been an evolutionary priority for four billion years. Nothing in the life sciences is more compelling than the mystery of how things move.

    In the beginning, there was a primordial Point A and Point B.

    Ever since, it has been the do-or-die imperative of all living creatures to get from one to the other.

    Even before Earth’s warm, salty broths produced the planet's first life forms around four billion years ago, scientists say that a gaggle of sophisticated molecules took their first baby-steps all their own in bringing forth all that would ever crawl, slither, run, walk, hop, skip, jump, swim, fly, croak or buzz.

    In fact, the entire panorama of evolution—from the spawn of the first feeble bacterium to man—can in one sense be seen as a history of how living things learned to move.

    Still, nature took its time in getting it right—the ability to move, that is. Scientists estimate that it took about two billion years after the spawn of life for things to start getting really interesting. Roughly a billion-and-a-half years ago, the simple cells of life's dawning began to give way to more complicated cells, with insides sporting all sorts of fancy organs and, in particular, a curious new breed of molecule—deoxyribonucleic acid, better known as DNA.

    This vast new family of one-celled critters—called protozoans—had another thing in common—they really knew how to move! Armed with an astonishing array of flailing, hairlike appendages, some of these single-celled creatures even today are still a relative match for any full-grown animal when it comes to speed, agility and versatility in getting around.

    Eventually, various tribes of wandering protozoans apparently discovered that they could get along better if they formed groups, or colonies. Over time, these new clusters of cooperative cells took on a life of their own, and the age of the multi-celled organisms—the metazoans—was born.

    In the brave new metazoan world, the capacity to move switched from being a mere novelty to a dire necessity. Once Earth’s surface was sufficiently covered in plants and other food, the race was on to fill the void, and the slow often got trampled—and eaten—in the process. Immense pressures of natural selection soon forged one of the greatest weapons for survival ever made—the muscle.

    From the tiniest bug to the biggest beast, muscles are clearly behind the wheel on life's highway. Marvels of biological construction no matter what their size, muscles have fascinated the only creature aware of their existence since the beginning of science. More than 300 years of study have produced a remarkable understanding of how muscles work. But some of the most fundamental answers remain secrets, presenting biologists with even more questions than they started with two centuries ago.

    A small group of scientists at Florida State have been so caught up in the mysteries of how muscles do what they do that they have made the study of these exquisite organs their life's work. These scientists’ curiosities go beyond the basic mechanics of muscles—which represent a molecular feat of spectacular proportions—and embrace the broader question of how any live organism, especially those born without the benefit of muscles, manages to move under its own power.

    What they have discovered so far has renewed scientists’ respect for the interconnectedness of all living organisms and fed a growing understanding of how animals convert food into useful work—a simple phrase with profound implications for the health and well-being of all God's creatures, both great and small.

    Gotta Crawl Before You Walk

    Imagine the glee that must have overcome Antoni van Leeuwenhoek (LAY-ven hoke), the Dutch inventor of the microscope, when he first trained his new gadget on a drop of pond water in the 1674.

    To his amazement, Leeuwenhoek saw a cavorting zoo of bizarre-looking forms which he soon dubbed "animalcules." This breathtaking discovery of a microscopic world of mobile creatures was revolutionary—for the first time, scientists had reason to believe that all animal life—from a flea to a human—propagated itself with the aid of moving, microscopic parts. The Dutchman’s subsequent observations of frantically swimming sperm cells (spermatozoa) dealt a powerful blow to the notion of "spontaneous generation"—which since ancient times had held that life forms literally sprang from the dust.

    Despite the insight more than three centuries of research has produced, today’s biologists still peer at pond water through microscopes and marvel at what they see.

    Dr. Tom Roberts (Ph.D. Notre Dame), head of FSU’s Department of Biological Science, says that only in the past 30 years have scientists come to fully appreciate the connection between moving microbes and moving muscles.

    "We now know that when we see individual cells divide and when we see them move we’re looking at the earliest beginnings of muscle development in multicellular organisms," Roberts said.

    Research since the late 1960s has proven that many of the molecular and mechanical processes which single cells use to swim, wriggle or crawl are in fact identical to those which run the muscular systems of all animals—including those without skeletons, he said.

    Whether an amoeba, a slime mold, an earthworm, a clam, a jellyfish, a squid, horse or chimp, each is endowed with the gift of movement that is driven by roughly the same set of biological chemicals that have been animating nature for eons.

    A parasitologist by training, for 25 years Roberts has studied how single cells crawl in amoeba-like fashion. Such work is of interest to the National Institutes of Health, which helps fund Roberts’ research, mainly because human health is both dependent on—and subject to—what millions of crawling cells within the body can do.

    Human blood, for example, contains four different kinds of cells, and three of them are proficient crawlers. Platelets are blood cells that swarm around cuts and other injuries, helping to keep us from bleeding to death and healing our wounds. Two different kinds of white blood cells attack and devour bacteria and other foreign invaders, representing the shock troops of our immune systems.

    Roberts’ work also has implications for understanding the behavior of cancer cells, whose fiendish abilities to crawl through healthy tissue can lead to devastating consequences. It’s the nightmare of every cancer patient to learn that their tumor has metastasized, or spread. In such cases, individual cancer cells break off the primary tumor, literally crawl their way through healthy tissues and enter the blood stream to be swept throughout the body. Wherever they settle, they can then crawl into healthy tissue and set up another deadly tumor.

    Roberts is perhaps best known for a 1978 discovery he and a colleague made during post-doctoral work at the Carnegie Institution in Baltimore. In studying the round, tail-less sperm cells of nematodes—a huge family of both parasitic and non-parasitic worms—Roberts was stunned to find out that the amoeba-like cells defied all conventional wisdom on the mechanics governing cell motility (see box above).

    Since those early days, Roberts’ lab has produced a healthy body of literature on his "strange cell" that lends fundamental insight into one of nature’s most perplexing and awe-inspiring feats—the self-propelled, purposeful movement of a boneless, muscleless, brainless blob of protoplasm.

The Basic Recipe for Locomotion

    Leeuwenhoek peered in wonderment at much more than pond water. He was the first to discover the stripes in ordinary muscle tissue.

    The function of such stripes, or striations—made up of bundles of individual fibers—soon led other scientists to assume that the secrets of movement lay in the remarkable abilities of these individual fibers to contract. It was a correct assumption that would take the next three centuries to fully explain.

    In 1947, Albert von Szent-Gyorgyi, a Hungarian biochemist, made a breakthrough discovery about how muscles work. With the knowledge that each muscle fiber, or cell, contains at least two prominent filaments, he found that both filaments work in concert to produce contraction.

    The thickest of the two filaments—myosin—had been isolated in the 1930s; Szent-Gyorgi himself had discovered the so-called "thin filament"—which he named actin—by 1940. Both filaments were found to be essentially chains of proteins which somehow worked together to produce force.

    In his findings, Szent-Gyorgi also confirmed a growing suspicion that an energy-rich compound extracted from muscles in 1929 called adenosine triphosphate, better known as ATP, was basically the chemical fuel that the two filaments used to operate the contraction machinery.

    But it would be left to an English molecular biologist in 1954, Hugh Esmor Huxley, to solve a riddle that had stumped researchers for years: How was it possible that neither actin or myosin—unquestionably the key filaments driving contraction—could cause muscles to contract within shrinking themselves?

    Applying electron microscopes and a technique called X-ray diffraction—in which molecules are bombarded with X-rays that reflect detailed clues of their atomic structure—Huxley found the secret of how actin and myosin filaments shorten muscle fibers without shortening themselves in the process.

    Huxley discovered that indeed the two filaments stay almost exactly the same length and simply telescope, or slide past each other inside a tightly confined space at the cores of muscle fibers. Actin filaments basically remain stationary, while myosin filaments slide down them, Huxley found.

    This sliding action, driven by the combustion of ATP, mechanically forces other filaments attached to the actin-myosin complex to squeeze together as a distinct unit called a sarcomere. Arranged like stacked sausages throughout the length of a muscle cell, sarcomeres squeeze themselves in unison when neurons deliver a contraction signal from the brain. The result is synchronized contraction that can shorten the entire length of a muscle in the blink of an eye.

    Huxley’s theory of sliding filaments, although raising a flurry of new questions, was the closest any scientist had come to presenting the full picture of how chemical energy (in the form of ATP) is converted to mechanical energy at the molecular level to produce movement.

    Molecular biologists since Huxley have piled intricate layers of knowledge onto the framework Huxley built, which still is considered the foundation of muscle mechanics. But for all this, scientists are still at a loss to fully explain the biomechanics of even the simplest movement, either in skeletal muscle or in a single crawling cell.

    They have, however, learned that almost all animal movement requires a recipe containing at least three biological ingredients—actin, myosin and ATP—which must be in the presence of some type of rigid or semi-rigid framework, or skeleton. Since Huxley’s day, cell biologists have discovered all three ingredients inside nearly every cell that can move—and scientists now concede that that means just about every living cell on the planet.

    Motion based on the actin-myosin interaction, fueled by ATP, is what propels protozoans’ whirling rows of hairlike cilia and whips their long flagella. It’s the basis of the adroit swimming skills of spermatozoa. It even drives the gelatinous "feet" of amoebae, which flow almost lava-like toward their prey.

    "Muscles are really just highly organized, highly specialized versions of something that has existed in cells a long, long time," says Roberts. "What our (muscle) group is finding here at FSU is helping to take that basic premise to a whole new level of understanding."

Skeletons High and Low

    The discovery that muscles always work in pairs and always pull—never push—dates to the 17th-Century findings of Italian physiologist Giovanni Borelli, who first applied the principles of mechanics to the study of animal movement. Since then, scientists have regarded the skeletons of all vertebrate animals (those with spines) basically as elaborately hinged racks for hanging muscles. Without bones or cartilage, such muscles have nothing to pull against to perform any work.

    Bony skeletons, by using joints as pivots, can harness the power of muscles to do an incredible variety of tasks, from lifting a piano to playing it. In every instance, pairs of muscles work in see-saw fashion—one pulling, or contracting; the other relaxing, standing by until a signal from the brain orders it to contract again.

    But animals are full of muscles that don’t bind to bone and don’t need to. Skeletal (or voluntary) muscle—the kind we use to get around—is independent of the types of muscles that digest our food and pump our blood. These are two classes of involuntary muscles—the kind that function without being told to. Smooth muscles help push food down our throats and through our intestines, literally churn our stomachs as a digestive aid and regulate our blood pressure in veins and arteries. Cardiac muscle envelopes the heart and keeps it beating.

    Animals without bony skeletons—and that includes most animals on Earth—manage to move primarily with variants of skeletal muscle. Insects, spiders, crabs, shrimp and other crustaceans have shells or other rugged outerwear that serve as external skeletons which they pull against to fly, crawl, leap and swim.

    Worms and a host of sea creatures such as jellyfish and sea anemones maintain their shapes with pressurized water, creating a hydrostatic skeleton. Mollusks, such as squid and octopuses, have "skeletons" literally made of crisscrossing bands of muscles that work against each other with unbelievable power, precision and speed. All mammalian tongues, as well as elephants’ trunks, move the same way.

    Biologists such as FSU’s Dr. Tom Keller explore the microscopic world of cellular skeletons, intricate latticeworks of filaments that, as it turns out, perform much of the same function for individual cells that tendon-lashed, skeletal superstructures perform in mammals.

    Keller’s focus is the curious realm of the cytoskeleton, an elaborate scaffolding of interlocking protein molecules that permeate the gooey insides of cells and gives them size and shape. Cytoskeletons are found in all cells except, apparently, bacteria. Whether in a single-celled paramecium or a blue whale, the ever-changing cytoskeleton not only controls how cells look, but controls their every function as well. From dividing to crawling, from organizing internal cellular functions and putting vital chemicals where they’re needed most, to giving the flesh of higher animals firmness and tone—the cytoskeleton does it all and then some, and as a consequence stands as one of nature’s supreme achievements.

    Quite by accident, in studying the cytoskeletal tissue extracted from chicken intestines in 1992, Keller made a discovery that bolstered theoretical ties linking the evolutionary history of locomotion in vertebrates to that of single-celled animals.

    Keller found long strands of a protein he later identified as titin, a gigantic protein that had been isolated in 1980 from skeletal muscles (see sidebar, page 25). By far the largest protein found in human cells, titin was thought to occur only in skeletal muscles where scientists believed it played a key role in muscle elasticity. Keller had found it in relative abundance in a single nonmuscle cell. What on earth was it doing there?

    "In hindsight, it’s not terrifically surprising that we found it where we did," he told Research in Review. "The titin we find in modern muscles is probably the most highly specialized form of a protein that was around long before muscles ever existed. It’s obviously one of the basic building blocks of the cytoskeleton even in much more primitive cells."

    Last January, the journal Science reported on Keller’s most recent findings on the giant molecule, specifically that titin helps give human platelets their flexibility and also is a component of the smooth muscle found in chicken gizzards.

    The latter finding surprises a lot of molecular biologists, but makes perfect sense to Keller. On the evolutionary scale, smooth muscle is considered the most primitive of all muscle types, and could well be the product of individual cells that fused long ago to form the first complex creatures ever to move.

Under the Hood of a Molecular Engine

    For all its insight, Huxley’s famous sliding-filament theory of the interplay between actin and myosin in muscle cells, stopped short of explaining the very essence of movement—the generation of the force behind it.

    Simple physics dictates that force is always the result of something pushing against something else. So what’s pushing against what to cause a muscle cell to contract? If ATP is the chemical fuel driving the sliding action between the actin and myosin filaments, exactly where and how is it burned, and what happens when it does?

    To get at such fundamental answers, muscle researchers today are armed with microscopes that Leeuwenhoek never dreamed of—along with other powerful tools that can probe the molecular world of living tissue. These machines, and the know-how to use them, have revolutionized research into fundamental muscle mechanics and have brought scientists much closer to a complete understanding of how muscles twitch and cells crawl.

    At the forefront of research into the molecular events that generate the force behind movement are Drs. Ken Taylor and Piotr Fajer, members of FSU’s Program in Structural Biology. Both scientists study the nuts-and-bolts of how protein molecules physically shift into gear as the cogs that literally drive the machinery of motion.

    Taylor (Ph.D. Berkeley), a specialist in the three-dimensional imaging and atomic modeling of protein molecules, is part of a collaborative team that involves scientists at Duke University, the University of Pennsylvania and at Cambridge. Collectively, the team represents more than 170 years of research into the molecular physiology of insect flight muscle. By the early 1960s, scientists had discovered that such muscle was the ideal candidate for studying muscle structure. The tissue’s components are arranged in an extraordinary orderliness that makes investigating their function much easier than studying them in vertebrate muscle, says Taylor.

    Is it possible that the path to fully understanding how muscles work in humans may lie through research on flying bugs? Taylor believes so.

    "This mechanism between actin and myosin (in the insects) is almost certainly the same," he said. "So what we find here would translate into vertebrate muscle and help us understand the mammalian system."

    The main muscle-bound insect the team studies is a large water bug, Lethocerus indicus, which Drs. Michael and Mary Reedy of Duke import from Thailand. Taylor began his collaboration with the Reedys, whose work in muscle structure is renowned, in 1980 after joining the Duke faculty. Before Duke, Taylor had "the best experience of (his) life" studying under Hugh Huxley, author of the sliding-filament theory, at Cambridge’s Laboratory for Molecular Biology. His Cambridge collaborator today is Richard Tregear, who, with Michael Reedy and others, published a seminal paper on muscle contraction in 1965, using the water bug as their model.

    "This is a very powerful group," says Taylor. "Each of us brings his or her own special talents, and quite frankly, I don’t think there’s any other place that can compete with us."

    Such a collaboration is necessary, says Taylor, primarily because of the variety of specialized expertise and labs required. The team’s central goal is to document in images, in as clear detail as possible, how the myosin and actin molecules physically move against each other to produce force. This requires a careful coalescing of information drawn from analyzing hundreds of insect-muscle specimens with 3-D electron microscopy and X-ray diffraction techniques.

    "Basically, what we do is try to catch glimpses of individual muscle proteins in the act of producing what we call the working stroke," says Taylor.

    Just as a camshaft pushes a piston in a gasoline engine, or a foot falls on a bicycle pedal, the working strokes of molecular engines are very real, though blindingly fast events. The paper Tregear and Reedy published in the journal Nature in 1965 was the first to show the true nature of a working stroke in progress between the filaments of actin and myosin.

    "The main goal of our research is to collect enough of these images to show conclusively where all the work is being produced in a working stroke of a molecular engine. There’s obviously a great deal we still don’t understand."

    Taylor’s primary contribution to the research effort is to combine and analyze images and data supplied to him by the Reedys and Tregear. His lab at FSU is thought to be the first to use a technique called tomography, the basis for medical CAT scans, to draw detailed, 3-D images of muscle molecules in action.

    Almost all of Taylor’s focus on the "working stroke" of the molecular engines inside insect flight muscle is trained on a specific portion of the myosin molecule—an oarlike extension that actually reaches out, locks onto, and "walks" down the actin filament. When it’s stationary, this part of the myosin protein is called its "head," but when it’s "walking" it’s better known as a crossbridge. These minute protrusions on the myosin protein are in fact the main moving part of a muscle’s molecular engine. In even the slightest twitch of a muscle, the number of crossbridges involved at any given instant can number into the billions. Taylor’s group specializes in getting stop-action pictures of one.

    To do that, the Reedys at Duke first slice ultra-thin layers of water bug flight muscle. Next, researchers at the University of Pennsylvania (Yale Goldman and Clara Franzini-Armstrong) use a device that gets the sliced muscle cells to contract just before they are fast-frozen in a liquid helium bath. The technique freezes countless individual crossbridges in various stages of interacting with the actin filament. The samples are then examined with electron microscopy, imaged in 3-D by tomography and analyzed by X-ray diffraction to generate information about the atomic structures of the key molecules involved in the contraction process.

    "When you stop to think about it, this is pretty amazing," says Taylor.

    Amazing indeed. The entire picture Taylor tries to capture is at least 10,000 times smaller than the width of a human hair. And it’s generated by a single molecule of myosin that may be changing shape at the rate of a dozen times a second.

    Across campus in his lab at the National High Magnetic Field Laboratory, Taylor’s colleague Piotr Fajer (Ph.D. Leeds) displays posters depicting his most recent interpretation of the molecular events going on at the crossbridge sites. Fajer, who describes himself a "physiologist at the molecular level," is also primarily interested in the force generation problem—how ATP is converted to mechanical energy.

    "I want to see how these molecules move, how the cellular function is affected by the movement of the smallest component (when ATP is burned)," he says.

    Unlike Taylor, Fajer doesn’t depend on 3-D images for his "snap-shots." He is among a small number of specialists in the world who use a technique called electron paramagnetic resonance, or EPR. Based on a similar principle behind MRI technology routinely used as diagnostic tools in hospitals today, EPR is extremely more sensitive and can be used to study the characteristics of individual molecules. The technique is so refined that Fajer says he can detect even the slightest changes in molecular movement. ("If something moves by half a degree, I can see it.")

    Fajer compiles and analyzes EPR data to show the subtle, but extremely important shape changes that the crossbridges undergo in what amount to a series of lightning-fast exchanges of chemical energy between myosin and actin. Scientists have known for some time that such exchanges instantly and dramatically contort the shapes of myosin and actin, along with other proteins intimately connected with both filaments. Ultimately, in muscle contraction it’s in this frenetic shape-changing process where the proverbial rubber meets the road in the course of movement, says Fajer. Not surprisingly, the devil is in a daze of details.

    "We know that the myosin filament rotates in such a way that it becomes strained (against the actin molecule), and causes the force, sort of like a spring," he said.

    But making the whole molecular engine work requires a no-miss, rapid-fire sequence of molecular contortions and energy exchange that defies precise understanding and thus requires considerable guesswork, he said.

    "In a car engine, you know that when gasoline burns it expands and pushes on the pistons. In muscles, we know that ATP gets burned. But exactly what moves with respect to what in order to produce force? The fact is, we really don’t yet know in any great detail, and that’s basically the goal of our research."

Thirsty Engines on the Edge of What’s Possible

    The common thread that binds all moving creatures is a thirst for energy.

    Long before scientists finally proved, in 1961, that it’s the dominant form of chemical fuel that drives muscle contraction, ATP has been the focus of intense research from many quarters. Drs. Timothy Moerland and Ross Ellington at FSU are biologists who track the flow of ATP and its assorted "helper molecules" from where they’re made in the cell to where they’re used.

    "Movement of any kind can be, and often is, extremely hungry energetically," says Moerland. "To get the energy it needs when it needs it, the body performs some pretty incredible feats."

    Moerland, who has studied the relationship between muscle weakness and poorly controlled diabetes, has a lofty regard for the energy supply-and-demand system that keeps muscles humming. In his latest research, funded by the National Science Foundation, he is chipping away at answers to questions that have baffled muscle researchers for decades.
 
    For example, Moerland is trying to lay out a framework of understanding the biochemical mechanics that allow an animal that’s at rest to suddenly burst into action in a flash. A frog sitting on a cool creek bank for hours, for example, can leap a dozen feet in an eyeblink when disturbed. A sleepy Airedale can bolt off a porch to scare the wits out of a mailman in a second flat.

    Such transitions from rest to extreme exercise require an energy supply system spread across a vast muscular network—a phenomenal complex that tends to warp credulity, says Moerland.

    "In situations like this, there can easily be a 100-fold or more rate of increase in energy consumption, and that’s at the whole-body level," he said. "When it’s scaled down to the actual cells doing the work, it can be a 1000-fold increase in some muscle types.

    "The bottom line is that the cells go on an energy-spending spree that’s just astonishing. Not only are you talking about a hundred- to a thousand-fold increase in the energy consumption rate, but this occurs literally on the order of a few milliseconds."

    Each muscle fiber, or cell, in vertebrate animals can be quite long—in a blue whale a single cell can stretch to 20 feet or more—and each fiber can contain hundreds of billions of sites that demand energy to coordinate movement. Most of these sites, which are myosin crossbridges, are regularly spaced along actin filaments. But the power plants of the cell where ATP is manufactured—organelles called mitochondria—aren’t regularly spaced, and in fact turn up almost willy-nilly in some cells, says Moerland.

    "So here you have a system where the places that burn the energy aren’t necessarily located right next to the places that supply the energy. So it’s not just a supply-and-demand problem, but a massive distribution problem—how in the world does ATP get to where it needs to be so quickly?"

    Complicating the fuel delivery system even more, Moerland says, is the morass of molecules clogging up the interior of every cell. In vertebrate animals, a typical muscle cell can contain upwards of a million items, ranging from bulky organelles like mitochondria to a soup of free-ranging chemical ions and a jungle of enzymes and other proteins.

    Moerland says that the key to the problem lies in diffusion, a fairly simple physical process whereby molecules migrate through and around things, driven by differences in pressure or electrical charges. But simple osmosis, the diffusion example typically demonstrated in middle school science labs, fails to explain the phenomenon in muscles.

    "Diffusion is easy to understand in a test tube or beaker, but how does it work in the incredibly complicated geometry inside a cell?"

    For answers to such questions, some researchers devise terribly complicated mathematical models that often are only loosely based on experimental evidence. Instead, Moerland uses a special diagnostic device at the NHMFL on campus to get direct information about how molecules travel through the maze of intracellular space.

    Moerland heavily relies on a technique similar to the one used by Fajer. At the NHMFL, Moerland exposes living muscle tissue extracted from goldfish to pulsed field gradient nuclear magnetic resonance. Moerland’s lab is one of only a few in the world to successfully use this method to study the molecular processes of ATP diffusion in live tissue, and it’s the first to examine the phenomenon in fish. With the technique, Moerland is able to actually "see" (with a lot of data analysis) molecules moving across and through membranes and other cellular obstacles.

    One of the key findings his research has turned up so far is evidence suggesting the existence of an elaborate "highway system" for ATP and other energy-related molecules to travel from the mitochondria, where they’re made, to the cell’s countless molecular engines. Last year, Moerland discovered that energy molecules move very rapidly down the length of a muscle cell, but have a hard time traveling across the same cell.

    "Longitudinal diffusion is relatively unimpeded, but we found that in trying to move in a sideways, or radial, direction, these molecules have a horrible time."

    But why do energy molecules need to travel against the grain, so to speak?

    Moerland says that because myosin crossbridges—the heart of muscles’ molecular engines—practically permeate muscle tissue, ATP must travel in all directions, and at once, for contraction to work. Crosstown crossbridges, so to speak, must be supplied just as much as those downtown—and at the same time.

    "You’ve got to have uniform distribution (of ATP) for the system to work," says Moerland. "So what we’re suggesting is that there may be a kind of highway system where these molecules literally have to go down, and turn right or left before they get to where they’re used."

    What Moerland is seeing may be one of the best examples of how nature found an albeit complicated way to deal with the most important element in movement—the continual, uninterrupted flow of energy. To Moerland, the seemingly impenetrable meshwork in which the cell’s energy system is obliged to function poses fascinating speculation about the existence of built-in limits on animal movement.

    By virtue of the fact that animals and cells not only can move, but can do so in stupefyingly adroit and often exquisitely beautiful ways, obviously the mechanics behind movement—despite their arcane complexity—work and work well, says Moerland. But he suspects the forces of evolution may have pushed the whole elegant shebang against the wall.

    "We can speculate that the highly integrated system we now see in muscle—the coordinating architecture of all muscle elements—is a compromise between various selective forces," he said. "I think we can say, pretty well, that this is a system that operates right on the edge of what’s possible."

Energy to Burn: The Kinase Key

    The clues that keep turning up in Ross Ellington’s research into energy consumption in animals add to scientists’ understanding of evolutionary biology. Ellington (Ph.D. Rhode Island) studies invertebrate animals, mostly marine species such as polychaete (POLY-keet) worms and sea urchins.

    The most rapid movement associated with such slow-moving creatures is in their sperm, which lie dormant until suddenly released directly into seawater. Ellington says that the sperm of some species, immediately on release, can swim rapidly for up to two hours in open water—a feat of endurance that dramatically underscores the versatility of a cell’s energy distribution system.

    And its complexity. Scientists have known since the 1930s that ATP, by itself, cannot sustain rapid movement that would keep a sperm swimming or an Airedale running. There’s simply not enough of it lying around in muscle tissue. So, nature devised an ATP back-up system that serves as a kind of "automatic overdraft protection" when demand for ATP threatens to exceed supply.

    In humans and other vertebrates, the back-up compound is creatine phosphate. In the animals Ellington studies, arginine phosphate, a related molecule, also serves as an ATP back-up. Both compounds are members of the large phosphagen family of organic chemicals and they basically work the same way, says Ellington. When all available ATP supplies are reach critically low levels, these chemicals combine with what’s left of the ATP molecule to make more ATP.

    But a tired cell can be bursting at the seams with phosphagen back-ups and still not be able to get energized, Ellington said. Yet another molecule is required as a spark to set off the reaction that turns the phosphagens and ATP residue into ATP. Collectively, these molecules are a group of enzymes called phosphagen kinases, and they serve as the essential catalysts that keep the ATP-fueled fires of a cell burning.

    Phosphagen kinases (PKs) represent a class of "behind-the-scene" molecular players that make all movement possible, says Ellington. Whether in the racing heart of a scared jackrabbit or the headlong plunge into seawater by wriggling sperm, PKs keep the levels of ATP high by swiftly converting all available supplies of phosphagens into the precious fuel of locomotion.

    In studying the large family of PKs, Ellington has developed a theory that may help explain at least part of the energy distribution phenomenon Moerland studies. Instead of randomly floating around the cytoplasm of muscle cells, PKs tend to be attracted to the very places where they are needed most, he says. This so-called "targeting" effect is nature’s way of handling energy distribution problems throughout the animal kingdom, he believes.

    "Whenever muscles start to contract or a flagellum starts to move, there’s a locally high concentration of these enzymes that comes into play," he said.

    Aside from what this targeting phenomenon means in the energy supply-and-demand equation, Ellington says his study of PKs helps trace the evolutionary history of life. He believes that such targeting is an extremely primitive biological function that has been around since the dawn of the metazoans. As evidence, his group recently isolated and cloned a type of creatine kinase (CK) found in the mitochondria of polychaete worms that both looks and acts exactly the same as the kinase found in the mitochondria of the human heart.

    "Humans and polychaetes last shared a common ancestor about 700 million years ago," he said. "Obviously, from an evolutionary standpoint there’s something very important about the way this molecule (creatine kinase) is built."

Bold Moves Ahead for Humanity, Science

    When muscles work the way nature intended, the pageantry of life is truly a thing of endless awe and promise. When they don’t, life can be pure, unrelieved hell.

    If modern medicine ever has a hope of defeating some of the most deadly and debilitating diseases that plague humankind, it will require great leaps in research to find the root causes behind a host of maladies that wreck the fragile molecular machinery of muscles.

    The failure of heart muscle alone kills more Americans each year than any other disease, for reasons that still baffle the best medical minds in the world. A particularly frightening heart problem is hypertrophic cardiac myopathy, a genetic disease with a nasty first symptom—victims drop dead for no apparent reason. The disease kills an inordinant number of young athletes—in 1990 it fatally struck Loyola Marymount basketball star Hank Gathers in the middle of a game.

    Other lethal or potentially lethal muscle disorders include a large family of muscle dystrophies (the worst being Duchenne’s MD); various kinds of paralysis, including tetanus (lockjaw); myasthenia gravis and related strength-sapping, autoimmune conditions; and an array of atrophying (wasting) diseases such as amyotrophic lateral sclerosis, better known as Lou Gherig’s disease. Most of these afflictions are genetically based. Most are also incurable and may likely be for generations to come.

    At the core of such intractable diseases is a wide range of basic research into the dynamics of molecular activity inside living cells, the scope of work under way in the labs of such scientists as Taylor, Roberts, Fajer, Moerland, Ellington and Keller at Florida State. If the promise of new medical tools such as gene therapy, for example, are ever realized in combating such diseases, chances are the road will be paved with such tools as 3-D electron microscopy, magnetic resonance spectroscopy and computational biology.

    Although of incalculable value, the worth of such work extends well beyond the prospects of alleviating pain and suffering among humans and their animal kindred.

    It will surely rank as one of science’s greatest triumphs to solve the final mysteries underlying the staggeringly complex phenomenon of mobility, in many ways as remarkable a product of evolution as the ability to think. The fact of the matter is, had animals never developed their awesome powers to move, they never would have had a chance to develop much more than a rudimentary brain.

    "If you’re not faster than whatever it is that wants to eat you, you aren’t going to make much of a contribution to the next generation," said Moerland. "Speed and efficiency—two of the cardinal attributes of natural selection. Millions of years of evolution crafted this system, and it works amazingly well."