Regenesis Page 2

  This focus on microbes and plants—especially on the overworked E. coli bacterium—may give rise to the impression that synthetic biology and genomic engineering have little to offer the charismatic megafauna—the higher organisms such as people. Nothing could be further from the truth. In fact these technologies have the power to improve human and animal health, extend our life span, increase our intelligence, and enhance our memory, among other things.

  The idea of improving the human species has always had an enormously bad press, stemming largely from the errors and excesses associated with the eugenics movements of the past. Historically, eugenics has covered everything from selective breeding for the purpose of upgrading the human gene pool to massive human rights violations against classes of people regarded as undesirable, degenerate, or unfit because of traits such as religion, sexual preference, handicap, and so on, culminating, in the extreme case, in the Nazi extermination program.

  Some proposals for enhancing the human body have had a harebrained ring to them, as for example the idea of equipping people with gills so that they could live in the sea alongside sharks. Burdened with past evils and silliness, any new proposal for changing human beings through genomic engineering faces an uphill battle. But consider this modest proposal: What if it were possible to make human beings immune to all viruses, known or unknown, natural or artificial? No more viral epidemics, influenza pandemics, or AIDS infections.

  Viruses do their damage by entering the cells of the host organism and then using the cellular machinery to replicate themselves, often killing the host cells in the process. This leads to the release of new viruses that proceed to infect other cells, which in turn produce yet more virus particles, and so on. Viruses can take control of a cell’s genetic machinery because both the virus and the cell share the same genetic code. However, changing the genetic code of the host cell, as well as that of the cellular machinery that reads and expresses the viral genome, could thwart the virus’s ability to infect cells (see Chapter 5).

  All this may sound wildly ambitious, but there is little doubt that the technology of genome engineering is in principle up to the task. An additional benefit of engineering a sweeping multivirus resistance into the body is that it would alleviate a common fear concerning synthetic biology—the accidental creation of an artificial supervirus to which humans would have no natural immunity.

  Genomic technologies can actually allow us to raise the dead. Back in 1996, when the sheep Dolly was the first mammal cloned into existence, she was not cloned from the cells of a live animal. Instead, she was produced from the frozen udder cell of a six-year-old ewe that had died some three years prior to Dolly’s birth. Dolly was a product of nuclear transfer cloning, a process in which a cell nucleus of the animal to be cloned is physically transferred into an egg cell whose nucleus had previously been removed. The new egg cell is then implanted into the uterus of an animal of the same species, where it gestates and develops into the fully formed, live clone.

  Although Dolly’s genetic parent had not been taken from the grave and magically resurrected, Dolly was nevertheless probably a nearly exact genetic duplicate of the deceased ewe from which she had been cloned, and so in that sense Dolly had indeed been “raised from the dead.” (Dolly was certainly different in the details of how the genome played out developmentally [a.k.a. epigenetically] but not so different as to discourage subsequent success in a variety of agricultural and research species.)

  But even better things were in the offing. A few years after Dolly, a group of Spanish and French scientists brought to life a member of an extinct animal species—the Pyrenean ibex, or bucardo, a subspecies of wild mountain goat whose few remaining members had been confined to a national park in northern Spain. The species had become extinct in January 2000, when the very last living member, a thirteen-year-old female named Celia, was crushed to death by a falling tree. Consequently the International Union for the Conservation of Nature (IUCN) formally changed the conservation status of the species from EW, which meant “extinct in the wild,” to EX, which meant “extinct,” period.

  Extinction, supposedly, was forever.

  But in the spring of 1999, Dr. Jose Folch, a biologist working for the Aragon regional government, had taken skin scrapings from Celia’s ears and stored the tissue samples in liquid nitrogen in order to preserve the bucardo’s genetic line. A few years later, in 2003, Folch and his group removed the nucleus from one of Celia’s ear cells, transferred it into an egg cell of a domestic goat, and implanted it into a surrogate mother in a procedure called interspecies nuclear transfer cloning.

  After a gestation period of five months, the surrogate mother gave birth to a live Pyrenean ibex. By any standard, this was an astonishing event. After being officially, literally, and totally extinct for more than two years, a new example of the vanished species was suddenly alive and breathing.

  Not for long, however. The baby ibex lived for only a few minutes before dying of a lung condition. Still, those scant minutes of life were proof positive that an extinct species could be resurrected, not by magic or miracles but by science.

  “Nuclear DNA confirmed that the clone was genetically identical to the bucardo’s donor cells,” the group wrote in its report on the project. “To our knowledge, this is the first animal born from an extinct subspecies.”

  Almost certainly, it will not be the last. The bucardo’s birth involved a bit of genomic reprogramming because the egg cell that developed into the baby ibex had not been fertilized by a sperm cell but rather by the nucleus of a somatic (body) cell. The nucleus and the egg cell had to be jump-started into becoming an embryo in a process known as electrofusion, which melds the two together.

  A later technique under development in my Harvard lab will allow us to resurrect practically any extinct animal whose genome is known or can be reconstructed from fossil remains, up to and including the woolly mammoth, the passenger pigeon, and even Neanderthal man. One of the obstacles to resurrecting those and other long extinct species is that intact cell nuclei of these animals no longer exist, which means that there is no nucleus available for nuclear transfer cloning. Nevertheless, the genome sequences of both the wooly mammoth and Neanderthal man have been substantially reconstructed; the genetic information that defines those animals exists, is known, and is stored in computer databases. The problem is to convert that information—those abstract sequences of letters—into actual strings of nucleotides that constitute the genes and genomes of the animals in question.

  This could be done by means of MAGE technology—multiplex automated genome engineering. MAGE is sort of a mass-scale, accelerated version of genetic engineering. Whereas genetic engineering works by making genetic changes manually on a few nucleotides at a time, MAGE introduces them on a wholesale basis in automated fashion. It would allow researchers to start with an intact genome of one animal and, by making the necessary changes, convert it into a functional genome of another animal entirely.

  You could start, for example, with an elephant’s genome and change it into a mammoth’s. First you would break up the elephant genome into about 30,000 chunks, each about 100,000 DNA units in length. Then, by using the mammoth’s reconstructed genome sequence as a template, you would selectively introduce the molecular changes necessary to make the elephant genome look like that of the mammoth. All of the revised chunks would then be reassembled to constitute a newly engineered mammoth genome, and the animal itself would then be cloned into existence by conventional interspecies nuclear transfer cloning (or perhaps by another method, the blastocyst injection of whole cells).

  The same technique would work for the Neanderthal, except that you’d start with a stem cell genome from a human adult and gradually reverse-engineer it into the Neanderthal genome or a reasonably close equivalent. These stem cells can produce tissues and organs. If society becomes comfortable with cloning and sees value in true human diversity, then the whole Neanderthal creature itself could be cloned by a surrogate
mother chimp—or by an extremely adventurous female human.

  Any technology that can accomplish such feats—taking us back into a primeval era when mammoths and Neanderthals roamed the earth—is one of unprecedented power. Genomic technologies will permit us to replay scenes from our evolutionary past and take evolution to places where it has never gone, and where it would probably never go if left to its own devices.

  Today we are at the point in science and technology where we humans can reduplicate and then improve what nature has already accomplished. We too can turn the inorganic into the organic. We too can read and interpret genomes—as well as modify them. And we too can create genetic diversity, adding to the considerable sum of it that nature has already produced.

  In 1903 German naturalist Ernst Haeckel stated the pithy dictum “Ontogeny recapitulates phylogeny.” By this he meant that the development of an individual organism (ontogeny) goes through the major evolutionary stages of its ancestors (phylogeny). He based this aphorism on observations that the early embryos of different animals resembled each other and that, as they grew, each one seemed to pass through, or recapitulate, the evolutionary history of its species. (For example, the human embryo at one point has gill slits, thus replicating an evolutionary stage of our piscine past.)

  While it is clear that embryos develop primitive characteristics that are subsequently lost in adults, Haeckel’s so-called biogenetic law is an overstatement and was not universally true when first proposed or today. However, I hereby propose a biogenetic law of my own, one that describes the current situation in molecular engineering and biotechnology: “Engineering recapitulates evolution.” Through human ingenuity, and by using the knowledge of physics and chemistry gained over the course of six industrial revolutions, we have developed the ability to manipulate and engineer matter, and by doing so we have rediscovered and harnessed the results of six similar revolutions that occurred during billions of years of biological evolution.

  Using nanobiotechnology, we stand at the door of manipulating genomes in a way that reflects the progress of evolutionary history: starting with the simplest organisms and ending, most portentously, by being able to alter our own genetic makeup. Synthetic genomics has the potential to recapitulate the course of natural genomic evolution, with the difference that the course of synthetic genomics will be under our own conscious deliberation and control instead of being directed by the blind and opportunistic processes of natural selection.

  We are already remaking ourselves and our world, retracing the steps of the original synthesis—redesigning, recoding, and reinventing nature itself in the process.

  ____________

  * Bacteria called Clostridium perfringens and Vibrio natriegens seem to be the world’s fastest doublers, reproducing in seven to ten minutes respectively.

  CHAPTER 1

  -3,800 MYR, LATE HADEAN

  At the Inorganic/Organic Interface

  What follows is the greatest story ever.

  It’s the story of a once invisible being, nameless for eons, now called “the genome.” Its being—its existence across time, its depth and complexity as a natural artifact, and the vast abundance and variety of its manifestations—is the story. It is ancient and modern, older than our oldest ancestor and yet fresher than a newborn baby. It has covered our planet with its descendants, now over a billion times a billion times a billion copies (1027).

  The tale of the genome involves more sex than the most pornographic novel imaginable. The narrative is replete with incredible action scenes, countless life-and-death struggles, wild improbabilities that turn out to be true, and overwhelming successes in the face of staggering odds. It is a story about families and universal truths. In the retelling, it becomes, in part, your own personal story. The tale reveals a vibrant past and may lead us to a better future. As the ultimate self-help manual, it offers better health and longer life, along with “descendants as numerous as the stars in the sky and as the sand on the seashore” (as in the Judeo-Christian-Islamic tradition), or “as numerous as the sands on the Ganges” (in Buddhism).

  As befits the greatest story ever, this is a multiplex tale, enacted and told in a spiral of understanding. Through its abundance, fidelity, and diversity, the genome adapted to the physical world, solving a small number of basic problems repeatedly, passing on the answers, and occasionally even rediscovering solutions once lost. We see these problems solved in the first instance biologically, by the process of evolution. Nature turned inorganic materials into organic substances. Natural organisms read and interpreted genomes. And natural organisms have created huge amounts of genetic diversity. That network of natural interactions comprises our first tale.

  It begins long ago, in the Hadean era.

  Can Organic Arise from Inorganic? Selection Among Atoms and Molecules

  The Hadean geologic era lived up to the image of an underworld inhabited by the ancient Greek god Hades—lifeless and full of hot lava—3.8 billion years ago. If a living cell were unfortunate enough to travel back through time to the Hadean landscape, it would be cooked: all water vaporized and its precious complexity of living stuff dry-roasted and then mineralized, turned from delicate, filmy proteins into charcoal (graphite), water vapor, and other waste products.

  Before this, all the way back to the big bang, the universe was made up almost entirely of hydrogen nuclei, the simplest of all elements, consisting of just one proton. These protons would collide and fuse together to form helium nuclei (2 protons). Inside stars these helium nuclei would in turn fuse to form carbon (6 protons). Carbon nuclei would then enter a cycle (the carbon-nitrogen cycle), taking in hydrogen, and by adding nitrogen (7) and oxygen (8) intermediates, would catalyze the formation of yet more helium. The new helium would, as before, make more carbon. The net outcome of all this is that in hot stars carbon catalyzes the formation of copies of itself. (By “catalyze,” I mean causing or accelerating a reaction without the catalyst itself undergoing a permanent change.)

  These thermonuclear transformations, which occur at Hades-plus temperatures within stars, are accompanied by the release of enormous amounts of energy in the form of radioactive particles such as gamma ray photons, positrons, and neutrinos. (And also of course by the heat and light that drive life on this planet.)

  The processes that make up the carbon-nitrogen cycle can be thought of as a form of natural selection for favorable reactions and stable elemental forms (atoms and their isotopes). This seems analogous to the mutation and selection of living species, and still later the mutation and selection of synthetic organisms. Today those five (hydrogen, helium, carbon, nitrogen, and oxygen) of the eighty stable elements are the most abundant in the universe. These processes selectively skipped over weakly represented lithium (3), beryllium (4), and boron (5).

  A list of such atomic elements (substances that chemically cannot be broken down further) is a prerequisite for understanding the next level of selection complexity—the combination of those basic atoms into the compounds (molecules) of nature. Antoine Lavoisier wrote the first comprehensive list of the elements in the first modern chemistry text, Traité élémentaire de chimie, in 1789. He listed thirty-one in all, together with light and “caloric” (heat), making up a total of thirty-three “simple substances belonging to all the kingdoms of nature, which may be considered the elements of bodies.” As Lavoisier presented them:

  Each element in the table above is followed by the abbreviation that is commonly used in most branches of science, and even within the general culture—for example, H2O (water), NaCl (salt), and CO2 (carbon dioxide). Jöns Jakob Berzelius, who developed an interest in chemistry in medical school, introduced these symbols in 1813. By 1818 he had measured the masses of forty-five of the eighty stable elements. As we will see in Chapter 3, as few as six elements may be sufficient to create the major molecules of life: S, C, H, P, O, N (sulfur, carbon, hydrogen, phosphorus, oxygen, and nitrogen—pronounced “spawn”—shaded gray in the table above). These consti
tute the most abundant elements in living systems; also needed are metal ions such as magnesium (Mg) that are involved in key reactions of these compounds.

  These elements chemically combined with one another to form molecules, such as water, as the newly formed earth cooled. How did life arise from nonlife? To understand this, we need to explore the universe of simple, nonliving chemicals. As far as we know, the physical and chemical properties of the elements are set largely by particles in the nucleus (as well as by those in the surrounding electron cloud), and not by the specific arrangement of those particles. For example, it matters only that there are six protons in carbon; the exact structural relationships among the protons are irrelevant. Those six protons, irrespective of how they are arranged in the nucleus, attract and retain an equivalent number of electrons in the surrounding electron cloud.

  In molecules, by contrast, the physical arrangement of the component atoms is crucial. For example, a molecule of water, H2O, is not just ten protons and ten electrons packed together randomly in a jumble. The order of the atoms and their shape matters. Water is not H-H-O but rather H-O-H, meaning that each hydrogen atom can only bind to the oxygen atom, and not to two atoms. Molecules are like intimate social networks. Some atoms, such as hydrogen, tend to make single bonds with only one other atom. Oxygen makes two bonds, nitrogen three, while an atom of carbon can bond with four other atoms. So, water has each hydrogen bonding with one atom, oxygen, and its oxygen bonding with two atoms.