How Did Life Begin?

By J. MADELEINE NASH/LA JOLLA

The molecule was not alive, at least not in any conventional sense. Yet its behavior was astonishingly lifelike. When it appeared last April at the Scripps Research Institute in La Jolla, California, scientists thought it had spoiled their experiment. But this snippet of synthetic rna -- one of the master molecules in the nuclei of all cells -- proved unusually talented. Within an hour of its formation, it had commandeered the organic material in a thimble-size test tube and started to make copies of itself. Then the copies made copies. Before long, the copies began to evolve, developing the ability to perform new and unexpected chemical tricks. Surprised and excited, the scientists who witnessed the event found themselves wondering, Is this how life got started?

It is a question that is being asked again and again as news of this remarkable molecule and others like it spreads through the scientific world. Never before have the creations of laboratories come so close to crossing the threshold that separates living from nonliving, the quick from the dead. It is as if the most fundamental questions about who we are and how we got here are being distilled into threadlike entities smaller than specks of dust. In the flurry of research now under way -- and the philosophical debate that is certain to follow -- scientists find themselves confronting anew one of earth's most ancient mysteries. What, exactly, is life, and how did it get started?

Science's answers to these questions are changing, and changing rapidly, as fresh evidence pours in from fields as disparate as oceanography and molecular biology, geochemistry and astronomy. This summer a startling, if still sketchy, synthesis of the new ideas emerged during a weeklong meeting of origin-of-life researchers in Barcelona, Spain. Life, it now appears, did not dawdle at the starting gate, but rushed forth at full gallop. UCLA paleobiologist J. William Schopf reported finding fossilized imprints of a thriving microbial community sandwiched between layers of rock that is 3.5 billion years old. This, along with other evidence, shows that life was well established only a billion years after the earth's formation, a much faster evolution than previously thought. Life did not arise under calm, benign conditions, as once assumed, but under the hellish skies of a planet racked by volcanic eruptions and menaced by comets and asteroids. In fact, the intruders from outer space may have delivered the raw materials necessary for life. So robust were the forces that gave rise to the first living organisms that it is entirely possible, many researchers believe, that life began not once but several times before it finally "took" and colonized the planet. The notion that life arose quickly and easily has spurred scientists to attempt a truly presumptuous feat: they want to create life -- real life -- in the lab. What they have in mind is not some monster like Frankenstein's, pieced together from body parts and jolted into consciousness by lightning bolts, but something more like the molecule in that thimble-size test tube at the Scripps Research Institute. They want to turn the hands of time all the way back to the beginning and create an entity that approximates the first, most primitive living thing. This ancient ancestor, believes Gerald Joyce, whose laboratory came up with the Scripps molecule, may have been a simpler, sturdier precursor of modern RNA, which, along with the nucleic acid DNA, its chemical cousin, carries the genetic code in all creatures great and small.

Some such molecule, Joyce and other scientists believe, arose in the shadowy twilight zone where the distinction between living and nonliving blurs and finally disappears. The precise chemical wizardry that caused it to pass from one side to the other remains unknown. But scientists around the world are feverishly trying to duplicate it. Eventually, possibly before the end of the century, Joyce predicts, one or more of them will succeed in creating a "living" molecule. When they do, it will throw into sharp relief one of the most unsettling questions of all: Was life an improbable miracle that happened only once? Or is it the result of a chemical process so common and inevitable that life may be continually springing up throughout the universe?

Of all the riddles that have stirred the human imagination, none has provoked more lyrical speculation, more religious awe, more contentious debate. No other moment in time, aside from the Big Bang that began the universe, could be more central to the understanding of nature than the instant that life began. "Scientific" theories on the subject are as old as civilization. The ancient Egyptians believed frogs and toads arose from silt deposited by the flooding Nile. The Greek philosopher Aristotle taught that insects and worms were born of dewdrops and slime, that mice were generated by dank soil and that eels and fish sprang forth from sand, mud and putrefying algae. In the 19th century, electricity, magnetism and radiation were believed to have the ability to quicken nonliving matter.

It took the conceptual might of Charles Darwin to imagine a biologically plausible scenario for life's emergence. In an oft quoted letter, written in 1871, Darwin suggested that life arose in a "warm little pond" where a rich brew of organic chemicals, over eons of time, might have given rise to the first simple organisms. For the next century, Darwin's agreeable hypothesis, expanded upon by other theorists, dominated thinking on the subject. Researchers decided that the "pond" was really the ocean and began trying to figure out where the building blocks of life could have come from.

In 1953 University of Chicago graduate student Stanley Miller provided the first widely accepted experimental evidence. In a glass jar he created a comic-strip version of primitive earth. Water for the ocean. Methane, ammonia and hydrogen for the atmosphere. Sparks for lightning and other forms of electrical discharge. One week later he found in his jar a sticky goop of organic chemicals, including large quantities of amino acids, Lego blocks for the proteins that make up cells. Case closed, or nearly so, many scientists believed.

Now this textbook picture of how life originated, so familiar to college students just a generation ago, is under serious attack. New insights into planetary formation have made it increasingly doubtful that clouds of methane and ammonia ever dominated the atmosphere of primitive earth. And although Miller's famous experiment produced the components of proteins, more and more researchers believe that a genetic master molecule -- probably RNA -- arose before proteins did.

Meanwhile, older and older fossils have all but proved that life did not evolve at the leisurely pace Darwin envisioned. Perhaps most intriguing of all, the discovery of organisms living in oceanic hot springs has provided a Stygian alternative to Darwin's peaceful picture. Life, says microbiologist Karl Stetter of the University of Regensburg in Germany, may not have formed in a nice, warm pond, but in "a hot pressure cooker."

If scientists have, by and large, tossed out the old ideas, they have not yet reached a consensus on the new. The current version of the story of life is a complex tale with many solid facts, many holes and no shortage of competing theories on how to fill in the missing pieces.

ONCE UPON A TIME

Some 4.5 billion years ago, the solar system took shape inside a chrysalis of gas and dust. Small objects formed first, then slammed into one another to create the planets. Early on, the energy unleashed by these violent collisions turned the embryonic earth into a molten ball. For a billion years thereafter, the young planet's gravitational field attracted all sorts of celestial garbage. Icy comets screamed in from the outermost reaches of the solar system, while asteroids and meteorites spiraled down like megaton bombs.

Some of these asteroids could have been the size of present-day continents, says planetary scientist Christopher Chyba, a White House fellow, and the asteroids' impact would have generated sufficient heat to vaporize rock, boil the oceans and fling into the atmosphere a scalding shroud of steam. Such a cataclysm would have obliterated all living things.

Yet after a billion years, when the solar system was swept nearly clean and the primordial bombardment ended, life was already flourishing. UCLA's Schopf has identified the imprints of 11 different types of microorganisms in the 3.5 billion-year-old rocks of Western Australia. Many of the fossils closely resemble species of blue-green algae found all over the world today. Still older rocks in Greenland hint of cellular life that may have come into existence a few hundred million years earlier -- perhaps 3.8 billion years ago.

At that time, scientists believe, life-threatening asteroids were still periodically pummeling the planet. Verne Oberbeck and colleagues at NASA Ames Research Center estimate that the interval between major impacts could have been as short as 3 million to 6 million years -- much too brief a time to give life a leisurely incubation. This means, says Oberbeck, that the chemistry needed to green the planet must have been fast, and it must have been simple. * That being the case, he asks, why wouldn't life have arisen more than once?

THE POINT OF ORIGIN

Where could life have sprouted and still been relatively safe from all but the largest asteroids? For the answer, many researchers are looking to strange, chimney-like structures found in the depths of oceans. These sit atop cracks in the ocean floor, known as hydrothermal vents, that lead to subterranean chambers of molten rock. The result is an underwater geyser: cold water plunges down through some of the cracks, and hot water gushes out through others. Fifteen years ago, when scientists began using submarines to explore these seemingly hostile environments, they were startled to discover extensive ecosystems filled with strange organisms, including giant tube worms and blind shrimp. Even more interesting, according to analysis of their RNA, the sulfur-eating microorganisms that anchor the food chain around the vents are the closest living link to the first creatures on earth. The only other life-forms that archaic are microbes living in surface steam baths like Yellowstone's Octopus Spring.

Could these overheated spots have been the places where life on earth got started? This "hot world" hypothesis has won many converts. Norman Pace, a microbiologist at Indiana University, speculates that the thin crust of primitive earth, as prone to cracking as an eggshell, would have made hydrothermal vents far more common than they are today. Geochemist Everett Shock of Washington University calculates that at high temperatures organisms can get extra energy from nutrients. "The hotter it is," says Shock, "the easier life is." (Up to a point. No one has yet found a microbe living in conditions hotter than 235 degreesF.)

Still, the question remains: Did life originate in the vents, or just migrate there? The vents may not have been a cradle but an air-raid shelter for organisms that originated near the ocean surface, then drifted to the bottom. There, protected by thousands of feet of water, these lucky refugees might have survived a series of extraterrestrial impacts that killed off their relatives near the sunlit surface.

THE INGREDIENTS

Stanley Miller's glass-jar experiment 40 years ago suggested that the components of life were easily manufactured from gases in the atmosphere. The conditions he re-created in his laboratory faithfully reflected the prevailing wisdom of the time, which held that the earth was formed by a gradual, almost gentle convergence of rock and flecks of dust under the influence of gravity. According to this model, the earth started out cold. Its deepest layers did not catch fire until much later, after the decay of radioactive elements slowly turned up the thermostat in the core. Thus, heavy elements such as iron did not immediately melt and sink to the core, but remained close to the surface for hundreds of millions of years.

Why is this important? Because iron soaks up oxygen and prevents it from combining with carbon to form carbon dioxide. Instead, the carbon, and also the nitrogen, spewed into the atmosphere by ancient volcanoes would have been available to interact with hydrogen. The serendipitous result: formation of methane and ammonia, the gases that made the Miller experiment go.

It was, says Chyba, "a beautiful picture." Unfortunately, he adds, it is probably wrong. For the violent collisions now believed to have attended earth's birth would have melted the iron and sent it plummeting to the depths. As a result, the early atmosphere would have been composed largely of carbon dioxide -- and organic compounds cannot be so easily generated in the presence of CO2.

Where, then, did the building blocks of life come from? Quite possibly, many scientists think, organic compounds were transported to earth by the very comets, asteroids and meteorites that were making life so difficult. At the University of California at Davis, zoologist David Deamer has extracted from meteorites organic material that forms cell-like membranes. He has also isolated pale yellow pigments capable of absorbing energy from light -- a precursor, Deamer believes, of chlorophyll, the green pigment used by modern plants.

But the amount of organic matter that can be carried by a meteorite is exceedingly small -- too small, many scientists believe, to have spawned life. For this reason, Chyba argues that a far more important source may have been interplanetary dust particles floating around in the era when earth was forming. Even today, he notes, countless tiny particles -- each potentially carrying a payload of organic compounds -- fall to earth like cosmic snowflakes, and their collective mass outweighs the rocky softball-size meteorites by a ratio of 100,000 to 1. Comets, black with carbon, could also have flown in some raw material. Whether it would have helped to spark life no one knows, since the chemical makeup of comets remains largely a mystery.

| And there's another possibility: big objects smashing into earth could have changed the composition of the atmosphere in significant -- albeit temporary -- ways. "Plow a big iron asteroid into earth," argues Kevin Zahnle of NASA Ames Research Center, "and you will certainly get interesting things happening, because all that iron is going to react with all the stuff that it hits." Such conditions, Zahnle speculates, might have briefly created the methane-filled atmosphere that Miller envisioned.

THE PRIMORDIAL CHEMISTRY LAB

Life's beginnings did not have the benefit of Miller's glass bottles, test tubes and vials. So how did nature bring the right ingredients for life together in an orderly fashion? One possibility recently suggested by Louis Lerman, a researcher at Lawrence Berkeley Laboratory, is that bubbles in the ocean served as miniature chemical reactors. Bubbles are ubiquitous, Lerman notes; at any given time, 5% of the ocean surface is covered with foam. In addition, bubbles tend to collect and concentrate many chemicals essential to life, including such trace metals as copper and zinc and salts like phosphate. Best of all, when bubbles burst, they forcibly eject their accumulated molecules into the atmosphere, where other scientists feel the most important chemistry takes place.

Biologist Harold Morowitz of George Mason University in Fairfax, Virginia, suspects that life arose in a less ephemeral chemistry lab than a bursting bubble. He focuses on Janus-faced molecules found in nature called amphiphiles. These molecules have one side with an affinity for water and another side that is repelled by water. Bobbing in the primitive oceans, the molecules would have hidden their water-hating sides away by curling into tiny spheres. These spheres, known as vesicles, would have provided an ideal setting for chemical reactions and could have been precursors to the first cells. "Once you have these little vesicles," says Morowitz, "you're on the way to life."

Which came first, though, the membrane or the metabolism? Gunter Wachtershauser, a patent attorney from Munich who also happens to be a theoretical chemist, believes that what we call life began as a series of chemical reactions between certain key organic molecules. Instead of being enclosed in a membrane, he says, they might have been stuck like pins in a cushion on the surface of some accommodating material. Wachtershauser's surprising candidate for this all-important material: pyrite, or fool's gold. Since the shiny crystal carries a positive electrical charge, it could have attracted negatively charged organic molecules, bringing them close enough to interact. Wachtershauser thinks these reactions could have led to the development of something similar to photosynthesis.

Still unanswered is the riddle of how these molecules came to reproduce. Chemist A.G. Cairns-Smith of the University of Glasgow thinks the answer may lie not in glittery fool's gold but in ordinary clay. The structure of certain clays repeats the same crystalline pattern over and over again. More important, when a defect occurs, it is repeated from then on, rather like a mutation in a strand of DNA. While few scientists believe such inorganic materials are actually alive, a number take very seriously the idea that clay or mineral crystals could have served as molecular molds that incorporated life's building blocks and organized them in precise arrays.

MOLECULAR ANCESTORS

Even if one accepts the fact that organic molecules can spontaneously organize themselves and, further, that these molecules might spontaneously reproduce, there remains a fundamental chicken-and-egg problem. Modern cells are made of proteins, and the blueprints for the proteins are contained in long strands of DNA and RNA. But DNA and RNA cannot be manufactured without an adequate supply of proteins, which act as catalysts in the construction process. How, then, could nucleic acids get started without proteins, or vice versa?

One solution was put forward a decade ago, when researchers discovered that certain RNA molecules can act both as blueprints and catalysts, stimulating reactions between themselves and other molecules. Up to that point, scientists had thought of RNAs as merely molecular messengers carrying genetic instructions from DNA to the cell's protein factories. Suddenly RNA was seen in a totally different light. If RNA could catalyze reactions, perhaps at some point in the past, it spurred its own replication. Then it could have been much more than DNA's intermediary: it could have been DNA's ancestor. According to this line of reasoning, the first organisms lived in an " RNA world," and DNA did not develop until life was speeding down the evolutionary turnpike.

While searching for that ancient precursor of life last April, Scripps Research Institute's Joyce stumbled on the molecule that so tantalized him. A bit of synthetic RNA sloshing around in a test tube suddenly attached itself , to a piece of protein and embarked on a course of nonstop replication. For a moment, this molecular upstart seemed close to the breakthrough Joyce had been seeking.

The molecule, he acknowledges, is not alive. Magical as it seems, it cannot replicate without a steady supply of prefabricated proteins. To qualify as living, a molecule would need to have the ability to reproduce without outside help. An important step in this direction was recently taken by Harvard molecular biologist Jack Szostak and his graduate student David Bartel, who mimicked the prolific chemistry of primitive earth by randomly generating trillions of different strands of RNA. Eventually the scientists came up with a good five dozen that were able to join themselves to other strands suspended in the same test tube. The process of linkage, explains Szostak, is critical to the formation of complex molecules from simple building blocks. What's exciting, he says, is this part of the origin-of-life puzzle does not look quite so daunting as before.

One of these days, both Joyce and Szostak believe, when someone fills a test tube with just the right stuff, a self-replicating molecule will pop up. If that happens, the achievement could be as upsetting as it is amazing. For it would challenge the most fundamental conceptions of what life is all about. Life, to most people, means animals or plants or bacteria. Less clear cut are viruses, because they are nothing more than strands of nucleic acid encased in protein, and they cannot reproduce outside a living cell.

As scientists close in on life's origins, the working definition of life will be pondered, debated and perhaps even expanded. If a sliver of fully functional RNA arises in a test tube and starts building its own proteins, who is to say it is any less alive than the strand of RNA doing the same thing inside a cell?

Some people will always hold to the belief that it is a divine spark, not clever chemistry, that brings matter to life, and for all their fancy equipment, scientists have yet to produce anything in a test tube that would shake a Fundamentalist's faith. The molecule in Joyce's lab, after all, is not as sophisticated as a virus and is still many orders of magnitude less complex than a bacterium. Indeed, the more scientists learn about it, the more extraordinary life seems. Just as the Big Bang theory has not demystified the universe, so progress in understanding the origin of life should ultimately enhance, not diminish, the wonder of it.

With reporting by David Bjerklie/New York, Barry Hillenbrand/London and James O. Jackson/Gottingen