Regenesis
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From the Prologue


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 jumpstarted 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 1000,000 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 reverseengineer 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.


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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 proces
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Errata

Page 63: "20N possible chains using the standard set and 39N".  Both instances of N should be superscripted.
Page 218-219: Balaena mysticetus, Arctica islandica, and Turritopsis nutricula  should be two words each.
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