Genetics of Original Sin Read online

  Earth formed a “cauldron” in which cosmic building blocks could interact

  From this naturalistic perspective, the products of cosmic chemistry are seen as landing in a milieu where some started interacting with each other to produce molecules of increasing size and complexity, which then interacted to produce polymolecular assemblages of increasing size and complexity, up to forming entities that could be defined as “protocells,” or primitive cells. Here is the snag. Nobody has so far succeeded in reproducing such a situation, or even a small part of it, in the laboratory.

  One problem is that there is no agreement yet on what may have been the milieu in which it all started. Some believe sunlight may have been needed as a source of energy. Others think that life originated in the darkness of deep waters. Debates also occur between proponents of a “hot cradle” and proponents of a “cold cradle.” According to the latter, the constituents of life are much too fragile to be able to survive long enough in a hot environment. The former, on the other hand, have been influenced by the fact that all the bacteria identified as most ancient by molecular phylogenies are thermophilic, that is, adapted to very hot environments.

  Another point of disagreement concerns the relationship between the early chemistry that led to life and present-day biochemistry. Many specialists, impressed with the total reliance of biochemistry on the activity of protein catalysts, or enzymes, which obviously are too complex to have been present at the dawn of life, argue that there is no relationship between the two chemistries. Some, however, including myself (see chapter 4), see biochemistry as flowing congruently from that early chemistry.

  As to the temperature that surrounded life’s birth, I adopt the opinion, held by a number of experts in the field, that life probably started in hot volcanic waters, perhaps in one of those underwater formations, called deep-sea hydrothermal vents, or black smokers, that spew overheated, pressurized, sulfurous, metal-laden waters from fissures in the bottom of oceans and have been found, against all expectations, to harbor many strange forms of life.

  My reason for subscribing to this view does not, however, rest on the thermophily of the most ancient bacteria, which are probably late products of a long evolutionary process and may not tell much about the conditions under which life first arose. I see volcanic waters as the likely site where life originated because present-day processes of biological energy transfer universally use derivatives of two central compounds, inorganic pyrophosphate and hydrogen sulfide, that are produced naturally only in a volcanic environment.

  The first steps in the origin of life were chemical in nature

  Whatever the pathways involved in those early stages, they must have been chemical in nature, which means that they were bound to happen under the physical-chemical conditions that prevailed where they took place. Chemistry deals with strictly deterministic, reproducible phenomena. Were it not so and should chemical processes involve even a tiny element of chance, there would be no chemical laboratories, no chemical factories. We could not afford the risk. Thus, if early events leading to the origin of life were chemical, as they must have been if our premise of a natural—and not supernatural—origin of life is correct, then they were bound to occur under the prevailing conditions. It follows that if the same conditions should occur elsewhere in the universe, one would sensibly expect life to emerge similarly there, an implication of interest with respect to a related question much in vogue: Does extraterrestrial life exist?

  This conclusion holds for all the early events in the origin of life, up to the appearance of the first information-bearing molecule capable of being replicated, that is, of inducing the making of copies of itself by whatever chemical machinery is responsible for making such molecules. As we shall see in chapter 7, this ability automatically entails the occurrence of selection, adding a new, chancy element to chemical determinism.

  The appearance of RNA was a key step in the origin of life

  In present-day life, the function of storing information in replicable form is universally fulfilled by DNA. There is, however, strong reason to believe that, in the origin of life, DNA has been preceded in this function by RNA, which also preceded proteins. To look into the arguments that support this opinion would take us into too many details. I mention it only in order to emphasize the crucial importance of the appearance of RNA in the origin of life, a veritable watershed separating a first stage exclusively dominated by chemistry from a second stage in which selection was added to chemistry (fig. 2.1). Experts in the field recognized this and have, in the last forty years, expended enormous efforts to try reproducing RNA synthesis under plausible early-Earth conditions. Many interesting results have been recorded; but the problem remains unsolved. Nobody has yet succeeded in making RNA in the laboratory, even under much more advantageous conditions than probably existed at the beginning of life. It could be said that a solution to this problem represents the “Holy Grail” of research on the origin of life.

  Making RNA would be only one of a long series of steps. Another, of fundamental importance, would be the birth of proteins, most likely through the operation of RNA molecules, which are universally responsible for the synthesis of proteins in present-day living beings. Proteins would inaugurate enzymes and, with them, metabolism. I shall return to these questions in greater detail in chapter 4, devoted to metabolism. In addition, the function of storing genetic information in replicable form would have to be transferred from RNA, with which it first arose, to DNA, which accomplishes it today. Finally, at some undetermined stage, these systems would have to become enclosed within an envelope, or membrane, to give rise to the first protocells.

  Fig. 2.1. The origin of life. This process may be defined as the chemical pathway, so far unknown, that has led from certain organic products, which form everywhere in the universe, to the last universal com-mon ancestor (LUCA) of all life on Earth. This pathway may be divided into two stages separated by the appearance of RNA (or, in a more general fashion, of the first replicable information-bearing molecule). The first stage must have depended exclusively on chemistry. In the second, selection was added to chemistry (see chapter 7).

  All these events must have taken place when life first arose on our young planet. How and in what order is totally unknown. Also unknown is the manner in which the first protocells progressively evolved into the last universal common ancestor of all living beings, or LUCA, which, must, by definition, have possessed all the main properties living organisms have in common and no doubt inherited from this common ancestor.

  There are plenty of challenges for future investigations. Whether these challenges will ever be successfully overcome cannot be predicted at this time. Today, the prospects seem bleak. On the other hand, experience has shown that a single breakthrough sometimes suddenly opens immense fields to scientific exploration. This has happened time and again, often with people exclaiming a posteriori: “Why didn’t I think of that?”

  3

  The Evolution of Life

  B orn more than three and a half billion years ago, life remained unicellular during more than two and a half billion years, more than two-thirds of its existence on Earth. During all that time, microbes, organisms visible only with a microscope, were the only ones present on our planet. They are still abundant, occupying a wide variety of sites and revealing their presence by many effects, such as producing diverse chemical substances, causing many infectious diseases, and putrefying dead organisms (a function they share with certain molds).

  Microbes have left few fossil vestiges but many other traces of their long duration on Earth

  Very few fossil remains landmark the history of microbes on Earth, but many other signs of their passage have been left. They remodeled their habitat, leaving many traces found in geological structures and in the atmosphere today. And they have undergone a number of changes that have become known to us through the study of the genomes of extant organisms. Three major events highlight this long history.

  Bacteri
a separated into two main groups

  First, the initial lineage soon split into two major groups, known today as Archaea and Bacteria or, more commonly, as archaebacteria and eubacteria, which, together, make up what much of the world still calls “bacteria” and experts designate as “prokaryotes,” organisms that do not possess a true nucleus (karyon in Greek).

  Archaebacteria, so named because they were believed, perhaps wrongly, to be the more ancient of the two groups, include, among many others, two particularly fascinating classes of extant microorganisms, the methanogens and the extremophiles.

  Methanogens are present wherever oxygen is absent and hydrogen is produced. There they survive by converting carbon dioxide (CO2) and hydrogen (H2) to methane gas (CH4) and water (H2O), a reaction that supplies them with enough energy to build their substance entirely from simple mineral building blocks. The mud at the bottom of ponds is one of their favorite habitats. The methane they produce in those murky depths creates the bubbles that break the silence of swamps by their muffled plopping; it fuels the will-o’-the-wisps that flit on the surface of marshes at night. Methanogens also thrive in the digestive tract of cattle and other ruminants. Methane is a greenhouse gas, which joins with carbon dioxide in the formation of the atmospheric shield that prevents heat from escaping and thereby contributes significantly to the warming of the global climate.

  Extremophiles, the other remarkable class of archaebacteria, include organisms that are, as their name indicates, adapted to extreme physical conditions: elevated temperature, up to more than 110°C (230°F), icy cold, high pressure, burning acidity, caustic alkalinity, concentrated brine, not counting the innumerable human-made pollutants. Extremophiles illustrate, more than any other living beings, the amazing ability of life to respond to environmental challenges.

  Eubacteria, the second group of prokaryotes, include most of the pathogenic varieties that cause such infectious diseases as tuberculosis, diphtheria, plague, leprosy, meningitis, pneumonia, and many others. They also comprise a large number of harmless varieties found in many natural niches, including the human gut, whose main inhabitant, E. coli (short for Escherichia coli, also known as colibacillus), has been the object of much of the seminal research leading to modern molecular biology.

  Atmospheric oxygen was a major contribution of life to Earth

  A second major event that took place during the “microbial era” is the appearance of molecular oxygen in the Earth’s atmosphere. Oxygen, the life-giving gas par excellence, was absent in the early atmosphere, as attested by multiple evidence in ancient rocks. LUCA and its descendants for more than one billion years were all “anaerobic,” which means that they lived without air, as many microorganisms still do today, for example, those that accomplish some of the fermentations on which we rely for the manufacturing of alcoholic beverages and cheeses. The early organisms, never having been exposed to oxygen, may even have been strict anaerobes, which are killed by this gas, as is the case for the bacillus of gangrene, which infects poorly aerated wounds and is readily killed by the simple device of incising the wounds and exposing them to air.

  What introduced oxygen into the Earth’s atmosphere was life itself, through the appearance of a special kind of photosynthetic bacteria called cyanobacteria (from the Greek kyanos, blue). These organisms use sunlight energy to split water (H2O) into hydrogen (H2) and oxygen (O2). The hydrogen is used to convert CO2 into sugar, from which, in turn, all the other organic cell constituents are formed, whereas oxygen is released in gaseous form.

  According to the geochemical evidence, the atmospheric oxygen level started rising about 2.4 billion years ago, up to, first, a value of 1 percent of the terrestrial atmosphere, reached some 2.2 billion years ago. It stayed at that level until a second upward move lifted it to its present value of 21 percent of the atmosphere, about 1.6 billion years later.

  The appearance of oxygen had a profound influence on the anaerobic forms of life that had been exclusively present until that time. Many disappeared, victims of oxygen toxicity, like the gangrene bacillus exposed to air. This extinction is sometimes referred to as the “oxygen holocaust,” a misleading term that suggests a sudden catastrophe that took place almost overnight. In fact, the process was exceedingly slow, with the oxygen content of the atmosphere rising by much less than one-ten-thousandth of a percent per millennium. There was plenty of time for life to adapt to the changing conditions.

  This adaptation probably took place first by the acquisition of enzymes capable of disabling oxygen. Such enzymes are present in all aero-tolerant organisms today. Eventually, some organisms not only protected themselves against oxygen but also acquired ways to take advantage of it. They developed chemical mechanisms whereby the energy released by the reaction of foodstuffs with oxygen could serve to support various kinds of biological work, much like fuel combustion supports motor-car engines and other heat-powered machines. The biological machineries, however, are “cold” engines; they convert oxidation energy into work without the mediation of heat. Most of life today is powered entirely (animals, fungi, many bacteria) or partly (plants and other photosynthetic organisms in the dark) by such engines, to the point that oxygen, from being a deathly menace, has become an indispensable condition of survival for much of life on Earth. The most sophisticated biological “combustion engines” are found in certain bacteria and in mitochondria, about which more soon.

  The birth of eukaryotic cells inaugurated a new living world

  The third major biological event that happened in those early days was the epoch-making birth of a new type of cells of much larger size and more complex structural and functional organization than their bacterial predecessors, conspicuously including a central nucleus containing the genome. Called “eukaryotic” (which is Greek for “having a good nucleus”), as opposed to the prokaryotic bacteria, these cells gave rise to a wide variety of unicellular organisms, known as protists, and also to all multicellular organisms, including plants, fungi, animals, and humans. So the prokaryote-eukaryote transition represents a watershed in the history of life on Earth, a key event on the way to our own appearance. Without it, our planet would still harbor only bacteria.

  Endosymbiosis was a key phenomenon in the development of eukaryotes

  Eukaryotic cells are so different from prokaryotic cells that one finds it difficult to imagine how one type could ever have arisen from the other. Yet, this is undoubtedly what happened, given the many indisputable signs of kinship between the two. Although the problem is far from solved, a number of telling clues are already available. Particularly revealing is the astonishing fact, now solidly established, that two key, granule-shaped organelles (small organs) of eukaryotic cells were once free-living bacteria that, at some time in the distant past, were taken up by other cells within which they underwent a progressive process of enslavement, turning into “endosymbionts” (literally meaning “living together inside”) and, eventually, evolving into fully integrated organelles.

  First to be adopted in this way were the mitochondria, which are the main sites of oxidative energy production, the central “power plants,” in the vast majority of eukaryotic cells. These organelles are derived from bacterial ancestors that must have ranked among the most efficient prokaryotic oxygen utilizers at the time they were adopted and have left similarly endowed, present-day descendants showing many signs of kinship with mitochondria.

  The second eukaryotic organelles of established endosymbiont origin are the chloroplasts, which harbor the light-utilizing systems of all photosynthetic eukaryotic cells, to wit, all unicellular algae and green plants. The bacterial ancestors of these organelles have been identified as belonging to the group of cyanobacteria, encountered above as the “inventors” of oxygen-generating photosynthesis. These ancestral organisms were first adopted by cells that already possessed mitochondria, which are thus present in all photosynthetic eukaryotes (except when lost in the course of evolution).

  For endosymbiosis to take place, t
here must first have existed cells with a size and functional properties that allowed them to harbor the bacteria that gave rise to the organelles. This question has been a fertile ground for all kinds of hypotheses, one more ingenious than the other. For my part, I stick to the simplest possibility, directly inspired by what we know and using a common cellular function, called “phagocytosis,” whereby, for example, white blood cells capture infectious bacteria that invade an organism. We need merely to suppose that a “primitive phagocyte” possessing this property already existed at the time we are talking about and that, exceptionally, the bacterial ancestors of the endosymbionts captured by this organism were not killed and destroyed, as happens in white blood cells, but survived to become the endosymbionts. Such a phenomenon would hardly be surprising, as several present-day instances of it are known. According to the hypothesis I propose, this phenomenon would have happened at least twice, first to the ancestors of mitochondria and then, again, to the cyanobacteria that evolved inside the host cell to become the chloroplasts.

  According to this scenario, formation of the “primitive phagocyte” from a prokaryotic ancestor appears as a crucial step in the development of eukaryotic cells. A detailed discussion of the manner in which this key transition could have occurred would take us too far. Let me simply emphasize the important role that may have been played by the passage from extracellular to intracellular digestion. All living beings that feed on nutrients provided by other living beings must start by digesting their foodstuffs, that is, cutting the big molecules of which these are made into small molecules that can be assimilated. This is what happens in our stomach and intestines. For single cells, this function is carried out in two different ways, depending on whether they are prokaryotic (bacteria) or eukaryotic. The former universally digest their foodstuffs with the help of enzymes that they discharge into their immediate surroundings, a process that requires prokaryotes to reside within their food source, like worms inside an apple or a piece of cheese. Eukaryotic cells, on the other hand, almost all feed by phagocytosis and digest their food within small intracellular pockets called “lysosomes”; they are thereby freed from the residential constraints to which bacteria are subjected. Thus, the development of the phagocytic mode of cellular feeding probably represents one of the key events in the birth of eukaryotic cells, the source of their emancipation and their ability to adopt endosymbionts.