Genesis: The Scientific Quest for Life's Origin

by Robert M. Hazen

  As we had hoped, a few workers in the origin-of-life community noticed our results. What we had not anticipated was significant interest from chemical engineers engaged in the design and purification of chiral pharmaceuticals. Our work on chiral mineral surfaces had opened the door to a host of possible industrial applications in the $100-billion-a-year chiral drug business.

  For our part, Glenn and I saw the aspartic acid study as the beginning of a long and fruitful collaboration. Next on the agenda were similar experiments with D- and L-glutamic acid, another amino acid that binds readily to calcite. We also plotted out new experiments with left-and right-handed quartz crystals. As our friendship grew, so did my interest in his other research projects, and he signed up my wife and me as field hands for his next Bahamain field season the following December.

  It was during these new experiments that Glenn, uncharacteristically, began to complain of an incessant pain in his jaw. A drug-resistant tooth infection had gradually spread through his mouth and into his sinuses. Worse than the pain, the disease numbed Glenn's sense of taste. He began to lose weight rapidly. He stopped drinking wine. In March of 2002, the antibiotic Cipro seemed to turn the tide. Glenn rallied and he even agreed to visit a favorite lunch spot, Pizza Paradiso, where for the first time in weeks he managed to eat most of his lunch. We talked optimistically of our December trip to the Bahamas.

  Though weakened, Glenn returned to his lab and began to recalibrate the sensitive analytical machines that had sat idle for so long. On March 27th, we enjoyed a brief, sobering visit from Steve Gould, whose magnum opus, On the Structure of Evolutionary Theory, had just appeared in print. Steve talked optimistically about the upcoming fieldwork, but he had just been diagnosed with a fast-spreading cancer and he tired quickly. During much of the visit, he sat in front of piles of his beloved Cerion, picking up one after another, pointing out unusual features. He kept saying “I need another 20 years. I just need another 20 years.” [Plate 8]

  But it was not to be. Stephen Jay Gould died of cancer on May 20th, fewer than two months later.

  By the end of May, Glenn's infection had returned with increased virulence, spreading to his brain, confusing his thoughts. During our last halting conversation, in early October, he fretted about the long hiatus in his research. He spoke eagerly of the December field trip to the Bahamas, as if in another few weeks he'd be well again. In his delirium, he anticipated meeting Steve Gould on the island.

  Glenn Goodfriend died on October 15, 2002, at the age of 51. The chance to know and work with him was one of the greatest gifts of my career, and his decline and death one of the saddest events I've ever had to experience. For months I was paralyzed by the loss. Asking anyone else to fill Glenn's shoes seemed disrespectful, like marrying again too soon after the death of a spouse. Colorful crystals lay idle in my lab. More than a hundred vials of amino acids sat unanalyzed. Only gradually, with the help of new collaborators, did the chiral-selection project get back on track.

  Scientists don't know for certain—and may never know for certain—how life's homochirality emerged from the random prebiotic milieu, but we have targeted an expanded repertoire of promising local chiral environments. Perhaps life's molecules self-select for handedness. Or perhaps they spontaneously assemble on chiral mineral surfaces. Whatever the answer, these ideas offer years of opportunities for origin-of-life researchers (and chemical engineers, as well).

  What we can say for sure at this stage is that mineral surfaces are remarkably successful at selecting, concentrating, and organizing organic compounds. Thanks to quartz, calcite, and a growing list of other crystals, the mystery of the emergence of organized molecular systems from the complex prebiotic soup seems a lot closer to being solved. It would appear that minerals played a far more central role in the origin of life than previously imagined. Armed with that understanding, chemists, biologists, and geologists are embracing a more integrated approach to one of science's oldest questions.

  Interlude—Where Are the Women?

  Reading your manuscript is really depressing. Where are the women?

  Sara Seager, 2004

  Even a cursory scan of this book reveals a field that has been overwhelmingly dominated by white males. Why should this be? Who's to blame?

  The answer certainly isn't in the nature of the discipline. A few scientific subjects, like field geology and high-pressure research, require extraordinary physical exertion and carry a level of risk that provided a convenient excuse for decades of almost exclusive male domination. But no such hardships are associated with research on life's origins, a field that holds intrinsic fascination for men and women alike. Yet hardly a single female appeared as coauthor on any origins paper in the three decades following Stanley Miller's 1953 landmark article.

  I don't know why, but I suspect that two factors played a significant role in this unfortunate, embarrassing bias.

  First, the origin-of-life field is small, and by simple bad fortune several of the most prominent leaders during the 1950s through the 1970s were male professors who were at best unsupportive of women students (if not downright misogynistic). All young scientists need the encouragement of mentors and the inspiration of role models. Lacking this support system, women felt excluded from the origins club. Only within the past decade has the research environment changed enough to provide women with a more conducive environment in which to excel.

  Second, the best and brightest women scientists may have shied away from the origins field in the beginning, when it held a rather dubious status in science. Everyone is interested in how life began, to be sure, but unambiguous experiments and firm conclusions are scarce. It was hard enough for many women to be taken seriously as scientists in the 1950s, 1960s, and even into the 1970s. No point in stacking the deck by entering a suspect area of research. Better to have concentrated on mainstream subjects like genetics or organic chemistry if you wanted to land a good job.

  Times have changed. More than 100 women scientists participated in the 2002 Astrobiology Science Conference at NASA Ames, while female enrollments in several astrobiology PhD programs are close to 50 percent. But our community must still look in the mirror and ask why it has taken so long.

  Part IV

  The Emergence of Self-Replicating Systems

  Four billion years ago, life began to emerge on an Earth hellish almost beyond imagining. Volcanoes poured rivers of lava onto the land and belched noxious sulfurous vapors into the atmosphere, while meteors fell in a fitful bombardment. Violent weather and epic tides lashed the primordial coastlines. Nothing remotely lifelike graced the desolate surface.

  Yet the seeds of life had been planted. The Archean Earth boasted vast repositories of serviceable organic molecules that had emerged from chemical reactions in the sunlit oceans and atmosphere, the depths of the crust, and the distant reaches of space. These molecules inevitably concentrated and assembled into vesicles, polymers, and other macromolecules of biological interest. Yet accumulations of organic macromolecules, no matter how highly selected and intricately organized, are not alive unless they also possess the ability to reproduce.

  Most experts agree that life can be defined as a chemical phenomenon possessing three fundamental attributes: the ability to grow, the ability to reproduce, and the ability to evolve. The first of these three characteristics, individual cell growth, has occurred on an all but invisible scale for most of Earth's history; for 3 billion years—from about 3.8 billion years ago to about 700 million years ago—the largest living organisms on Earth were microscopic single-celled objects. The third characteristic, evolution, proved to be slow and subtle: It took billions of years for cells to learn some of the most familiar biochemical tasks, such as using sunlight for energy or oxygen for respiration. But reproduction, life's most dynamic overriding imperative, must have operated with an inexorable, geometric swiftness. In the geological blink of an eye, rapidly reproducing populations of cells doubled and redoubled, spreading through Earth's oceans, colo
nizing and transforming the globe. Reproduction, more than any other characteristic of life, set the world of life apart from the prebiotic era.

  For origin-of-life researchers, creating a self-replicating molecular system in a test tube has become the experimental Holy Grail. It has proved vastly more difficult to devise an experiment to study chemical self-replication than to simulate the earlier stages of life's emergence—prebiotic synthesis of biomolecules, or the selective concentration and organization of those molecules into membranes and polymers, for example. In a reproducing chemical system, one small group of molecules must multiply again and again at the expense of other molecules, which serve as food. It's an extraordinarily difficult chemical feat, but the rewards for success are immense. Imagine being the first scientist to create a lifelike chemical system in the laboratory!

  14

  Wheels Within Wheels

  The origin of metabolism is the next great virgin territory which is waiting for experimental chemists to explore.

  Freeman Dyson, Origins of Life, 1985

  Scientists who study life's origins divide into many camps. One group of researchers claims that life is a cosmic imperative that emerges anywhere in the universe if conditions are appropriate, while their rivals view life on Earth as a chance (and probably unique) event. One camp claims that some sort of enclosing membrane must have preceded life; another counters with models of “flat” surface life. Some researchers insist that life's origin depended on solar energy, while others point to Earth's internal heat as a more likely triggering source. Lacking adequate observational or experimental evidence to arbitrate these divergent views, positions sometimes become polarized and inflexible.

  Perhaps the most fundamental of the scientific debates on origin events relates to the timing of two essential biological processes, metabolism and genetics. Metabolism is the ability to manufacture biomolecular structures from a source of energy (such as sunlight) and matter scavenged from the surroundings (usually in the form of small molecules). An organism can't survive and grow without an adequate supply of energy and matter. Genetics, by contrast, deals with the transfer of biological information from one generation to the next—a blue-print for life via the mechanisms of information-rich polymers, such as DNA and RNA. An organism can't reproduce without a reliable means to pass on its genetic information.

  The problem as it relates to origins is that metabolism and genetics constitute two separate, chemically distinct systems in today's cells, much as your circulatory and nervous systems are physically distinct networks in your body. Nevertheless, just like your blood and your brains, metabolism and genetics are inextricably linked in modern life. DNA holds genetic instructions to make hundreds of molecules essential to metabolism, while metabolism provides both the energy and the basic building blocks to make DNA and other genetic materials. Like the dilemma of the chicken and the egg, it's difficult to imagine a time when metabolism and genetics were not intertwined. Consequently, origin-of-life researchers engage in an intense ongoing debate about whether these two aspects of life arose simultaneously or independently and, if the latter, which one came first.

  Most experts seem to agree that the simultaneous emergence of metabolism and genetics is unlikely. The chemical processes are just too different, and they rely on completely different sets of molecules. It's much easier to imagine life arising one small step at a time, but what is the sequence of emergent steps?

  Those who favor genetics as the first step argue in part on the basis of life's incredible complexity. They point to the astonishing intricacy of even the simplest living cell. Without a genetic mechanism, there would be no way to ensure the faithful reproduction of all that complexity. Metabolism without genetics, they say, is nothing more than a bunch of overactive chemicals. Biologists, who must deal with complex cells and whose academic curriculum is dominated by the powerful, unifying spell of the genetic code, seem inclined to adopt this view without reservation.

  Other scientists, myself included, tend to be more influenced by what we perceive as the underlying chemical simplicity of primitive metabolism. We are persuaded by the principle that life emerged through stages of increasing complexity. Metabolic chemistry, at its core, is vastly simpler than genetics, because it requires relatively few small molecules working in concert to duplicate themselves. Harold Morowitz and Günter Wächtershäuser, among others, agree that the core metabolic cycle—the citric acid cycle, which lies at the heart of every modern cell's metabolic processes—survives as a chemical fossil almost from life's beginning. This comparatively simple chemical cycle is an engine that can bootstrap all of life's biochemistry, including the key molecules of genetics.

  We conclude that if life arose through a sequence of ever more complex emergent steps, then bare-bones metabolism seems the more likely precursor. Such a no-frills metabolic system, furthermore, might easily be enclosed in a primitive membrane of the type David Deamer makes in his lab. My sense is that many chemists, physicists, and geologists (not many of whom deal with DNA on a regular basis) are persuaded by this metabolism-first point of view.

  Origin-of-life scientists aren't shy about voicing their opinions on the metabolism-first versus genetics-first problem, which will probably remain one of the hottest controversies in the field for some time. Meanwhile, as this debate fuels animated discussions at conferences and in print, several groups of researchers are attempting to shed light on the issue by devising self-replicating chemical systems—metabolism in a test tube.

  SELF-REPLICATING MOLECULES

  The simplest imaginable self-replicating system consists of a single molecule that makes copies of itself. In the right chemical environment, such an isolated molecule will become two, then four, then eight molecules and so on in a geometrical expansion. Such a molecule is autocatalytic—that is, it acts as a template that attracts and assembles its own components from an appropriate chemical broth. Single self-replicating molecules are intrinsically complex in structure, but organic chemists have managed to devise several varieties of these curious beasts.

  Self-replicating molecules catalyze their own formation from smaller building blocks. In this example, one molecule AB plus individual A and B molecules combine to make new AB molecules.

  Self-replicating molecules possess a distinctive feature known as self-complementarity. Pairs of complementary molecules—molecules of different species that fit snugly together because of their shape and the arrangement of their chemical bonds—turn out to be relatively common in nature. Many of the proteins in your body, for example, function because they are complementary to food, neurotransmitters, toxins, or other molecules of biological importance. For this very reason, the synthesis of complementary molecules has become a central task of computer-aided drug design. If you can design a molecule that fits into pain receptors and thereby blocks pain signals, you can make a lot of money. Only a handful of known molecules are self-complementary, however, and even fewer can self-replicate.

  Hungarian-born chemist Julius Rebek, Jr., now at the Scripps Research Institute in La Jolla, California, has spent many years designing such molecules. In 1989 Rebek's group employed three smaller molecules: the purine adenine; the two-ring cyclic molecule napthalene; and imide, a nitrogen-containing compound. When bonded end-to-end, the resulting adenine–napthalene–imide molecule is self-complementary and, if immersed in a solution containing lots of these three individual molecules, will make copies of itself.

  Reza Ghadiri, leader of another productive research group at the Scripps Institute, focuses on yet another chemical system—self-replicating peptides, which are arguably much more relevant than most other molecules when it comes to the origin of life. Peptides, like proteins, are chainlike molecules built from long sequences of amino acids; their constituents are drawn from the same library of 20 amino acids that make up proteins, but they are typically dozens instead of hundreds of amino acids long. In 1996, Ghadiri's group reported the first synthesis of a self-replicating
peptide—a sequence of 32 amino acids. For self-replication to occur, however, this peptide had to be “fed” two reactive fragments, one of them 15 and the other 17 amino acids long. Given a steady supply of these two precursor fragments, new peptides formed spontaneously.

  Self-complementary strands of the genetic molecule DNA display similar self-replicating behavior. As James Watson and Francis Crick famously discovered in 1953, the classic double-helix structure of the DNA molecule is like a long, twisted ladder, whose vertical supports are chains of alternating phosphate and sugar molecules and whose rungs consist of the complementary pairs of molecules called bases: Cytosine (C) always pairs with guanine (G), while adenine (A) always pairs with thymine (T). Consequently, a single DNA strand with the base sequence ACGTTTCCA, say, is complementary to a second single strand TGCAAAGGT. When the two strands separate, each can then make a copy of the original double helix—as noted in one of the most celebrated and oft-quoted sentences in the history of biology, from Watson and Crick's landmark paper: “It has not escaped our attention that the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material.”

  The double-helix structure of DNA features two complementary sequences of the bases A, C, G, and T. A always binds to T, while C always binds to G. The molecule replicates by splitting down the middle and adding new bases to each side. Thus, one strand becomes two.

  The vast majority of DNA strands are not self-complementary, because the two halves of the double helix have different base sequences. But in 1986, German chemist Guenter von Kiedrowski and co-workers synthesized the first of the so-called “palindromic,” self-complementary DNA strands—the six-nucleotide sequence CCGCGG, which makes exact copies of itself if sufficient supplies of fresh C and G are provided.