Authors: Adam Rutherford
Of course, a Friesian cow or Savoy cabbage are both life-forms that are extremely unlikely to have existed naturally. They have been bred over innumerable generations for the express purpose of amplifying desirable characteristics: milky udders or a crunchy taste. I doubt anyone would accuse your average farmer of creaking open profound doors.
Did Venter create life? In a very particular sense, yes. But in most others, no. Certainly, Synthia did not exist as a living thing until Venter's team booted it up in a plastic tube. Its genome was created on a computer and then in a machine fed with four bottles containing the raw letters of genetic code. It was not derived from the biological replication of an existing genome copying itself using the method that has served life for billions of years. But the sequence itself, modified with genetic fail-safe suicide switches and pretentious (mis)quotations, was replicated from an existing species. And the chassis into which the synthetic genome was placed was from an existing cell from a naturally existing species, one distinctly embedded in the firmly rooted tree of life. What Craig Venter and his team did was to re-create a life-form synthetically. That is undoubtedly a huge achievement in itself. It's another incremental step on the pathway to having total control over DNA, and our ability to manipulate life.
The second thing that Venter's endeavor reveals is how poorly understood and misrepresented this nascent field is. We have been tinkering with living things for tens of thousands of years, though never before with such molecular precision. The pace of progress has been breathtaking. A decade ago I finished my PhD in genetics, during which time I was doing minor acts of genetic tinkering in order to work out how the eye develops, and why in some families it goes wrong, leading to children born blind. The types of experiments I was doing then can now be done by undergraduate scientists and even hobbyists known as biohackersâamateurs, sometimes of school age, who mix the genes and DNA of organisms in garages on weekends. This in one sense is natural progress, where new technologies become normalized and the exclusivity that comes with expertise or invention is lost as they become standardized tools. But the pace of that transfer is daunting, and poorly understood outside the world of science. And in the right (or worse, wrong) atmosphere, people fear what they don't understand. As the story of Craig Venter and Synthia shows, extraordinary science can result in visceral reactions.
What follows is a snapshot of this embryonic field of the engineering of living things. The synthetic biologists have application in mind, engineered and constructed solutions to the problems that this planet faces, and, more incredibly, the tools to explore beyond our earthly shackles. Many of the applications of the creations described here are speculative, but they are nevertheless built with purpose in mind. With the advent of these creations, we stand on the precipice of a new industrial revolution. The wood, iron, and coal that drove the industrial revolution of the eighteenth and nineteenth centuries was drawn from natureâcut, mined, and extracted from the world. But in use they were rendered inanimate and dead. This time around, the agents of change are not just taken from the natural worldâthey are alive.
Created, Not Begotten
“I am against nature. I don't dig nature at all. I think nature is very unnatural.”
Bob Dylan
F
reckles looks like a perfectly normal kid. She has bright eyes, a healthy white pelt, and gambols happily with Pudding, Sweetie, and her five other siblings, exactly as you might imagine a young goat would. Until I fend her off, she's very keen on chewing on my trousers. To the casual observer, and to professional goatherds, she shows no signs that she is not a perfectly normal farmyard goat.
In fact, Freckles is utterly extraordinary. While almost all of her genome is what you would expect a goat to have, there is a foreign corner in her DNA taken from
Nephila clavipes
, the golden orb-weaver spider. The language of the DNA is exactly the same in both goats and spiders, as it is in all living things, but the translation of that particular piece of code is very alien to your average goat. It has been inserted at a very specific point in Freckles's genome, adjacent to a coded instruction that prompts the production of milk in her udders. As a result of this genetic intrusion, when Freckles lactates, her milk is replete with spider silk.
Freckles is the creation of a team of scientists from Utah State University led by Randy Lewis. I visited their lab, which is in fact a farm at the base of a daunting mountain range in Logan, Utah. Though a long way from the sterile, clean rooms of a typical molecular biology lab, this setting is apt enough; Lewis and his colleagues are in a sense the most advanced farmers in the history of our species. It is dragline silk they are interested in, the gossamer fiber that spiders use to swing from when descending. This material has stunning physical properties, with a combination of strength and elasticity unsurpassed by anything that humans can yet manufacture. The orb-weaver genus has existed since the Jurassic period, which began around two hundred million years ago, and during the epochs before and since evolution has conspired to bestow a product on these spiders that is so far beyond humankind's greatest efforts, but which the spider produces in bulk without a thought. We can make fibers with strength or with great elasticity, but not with both. That is why Freckles exists, the unnatural creation of scientists.
For more than ten thousand years, since the dawn of agriculture, we have identified appealing characteristics of the natural world and attempted to enhance and exploit those properties. This is farming, a process that is at heart the precise opposite of natural selection, though it harnesses the exact same means. Instead of survival determining what unintelligently designed adaptations evolve, we choose characteristics that we find attractive and breed species to optimize production of that trait, whether it is fruit or land used to grow crops; livestock for meat, dairy, or leather; or dogs and plants bred for behavior or aesthetics. Farming is evolution by design.
Until the era of genetic engineering, this artificial selection has been inherently limited by natural boundaries. Although notoriously difficult to pin down precisely, one definition of a species is a group of organisms that, when crossed with one another, can produce fertile offspring. It's not a wholly infallible definition, and the process by which that barrier is introducedâspeciationâis one of the great questions in biology. But from the point of view of a farmer, the limitations of the species barrier are unsurpassable. In simple terms, you can't mate a pig with a cow.
Desirable traits are introduced over time by careful selective mating over generations, a fact well known to Charles Darwin. The opening chapter of
On the Origin of Species
is devoted not to his central thesis of evolution by natural selection but to artificial selection in pigeons. In this pigeon section Darwin is demonstrating that species are not immutable, that they can change over generational time. The birds he describes had been reared over thousands of generations by competitive fancy breeders to feature ever more preposterous prize-winning plumes, gullets, and feet, such that they had names like Trumpeters, Fantails, Tumblers, and Pouters. Through meticulous observation of their skeletons, and in direct opposition to the forcefully held opinions of the pigeon men, Darwin correctly revealed that these pigeons were all still varieties of the same species, the rock dove
Columba livia
.
With the discovery of the genetic code and with the advent of our ability to manipulate it, we are now capable of fully circumventing the limitations of evolution and radically violating the species barrier. Freckles, though by no means extraordinary in terms of genetic modification techniques available now, is a dramatic example of this biological infringement. Pigs and cows are both mammals, both even-toed ungulates and closely related in evolutionary terms with each other and with camels, giraffes, and hippopotamuses. Their common ancestors existed a few tens of million years ago, an evolutionary blink of the eye. Yet that distance is enough to forefend viable offspring if they were to attempt mating. This barrier is laid down by diverging genetic incompatibilities, though the physical congress is conceivable. A few closely related beasts do produce viable children, such as zeedonks, ligers, and hinnies, though these hybrids tend to be infertile and therefore evolutionary cul-de-sacs as they cannot themselves reproduce.
1
The last common ancestor of a spider and a goat would have existed something like seven hundred million years ago, at a time when the beings that would acquire hard shells, such as insects and crustaceans, were evolving away from creatures with fleshy exteriors, such as the fishy or reptilian beasts that would eventually lead to us. As the tree of complex life only grows via diverging branches, spiders and goats have not exchanged genes or DNA since that time. Unlike a zebra and a donkey (or even a pig and a cow for that matter), sexual union of a spider and a goat is obviously physically impossible. But the DNA code they both carry is the same across all known life-forms. It is the same language, formatted in the same way so that the tools and mechanics of the translation of that code are blind to its cryptic meaning. Thus, if a spider dragline silk gene is introduced into a goat genome in a way careful enough not to disrupt essential biology, the goat's cellular machinery will produce spider silk without reference to its aberrant origin.
And that is exactly what happens in Freckles's udders. In spiders, dragline silk is made of short strands of protein, which align and self-assemble as they are pushed or drawn out of the spider's spinneret. Proteins themselves are long strings of molecules called amino acids, and the very specific combinations of amino acids in silk fibers mean that they line up and overlap one another, locking into continuous threads that have built-in give. Because of this, they have length, strength, and elasticity. Randy Lewis's goats produce the short silk proteins in abundance, which float freely in the milk. The fat is removed from the milk, which is then pushed through a high-pressure processor. From there, with just a glass rod, I lift a single thread of spider silk from the goat's milk, and the noses and tails of the shorter fibers link together as I draw them from the liquid. It is strong enough to wind onto a spool by the foot. As yet, this unnatural silk does not quite have the same elastic or tensile strength as that created by spiders themselves. The research continues.
Although seemingly bizarre, this process is effectively next-generation farming. Its physical properties make spider silk an extremely desirable substance for humankind. It is tougher than the man-made fiber Kevlar used in body armor and puncture-proof tires. It is also a substance that does not generate a significant immune system response and remains insoluble in water, two facts that the classical Greeks exploited when they used cobwebs to patch bleeding wounds. These properties mean that spider silk has great potential for ligament repair, for which medicine currently uses either slivers of flesh extracted from the patient's own muscles or tissue from dead bodies. Neither of these solutions is permanent, so we could do with a replacement ligament made of a biologically neutral substance that has physical strength equal to or better than our own ligaments.
It might seem absurd to say it, but spiders cannot be farmed. When kept in groups they have a tendency toward cannibalism. With our ability to violate natural species boundaries using the tools of modern genetics, we are able to harvest a product by placing its code in a farmable animal. Although Freckles the spider-goat is a striking example of our prowess with gene mixing, she is not at all unique. This is genetic engineering: the creation of unnatural life using evolution's bountiful toolbox.
The language of DNA is carried by all living things because life on Earth ultimately evolved from a single origin, a cell that existed around four billion years ago.
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The language, code, and mechanics of all living cells are all the same. DNA bears a hidden language, which is decoded via a messenger molecule called RNA, which is translated into proteins. Proteins carry out all the functions of life, as enzymes that speed up essential biochemical reactions inside our cells to provide us with vital energy, or as missives such as hormones that carry instructions from one part of the body to another. Proteins form structures that hold our cells together, and they fabricate other structures such as bone, teeth, and hair. In short, all life is built from or by proteins.
Because of this common origin and universal process, the cellular mechanics of reading and translating the code of DNA are both blind and indifferent to its meaning, which means that the code of living things can be used to transgress the natural barriers of reproduction. Chimeras such as Freckles are called transgenic organisms, as the genes have been moved across the species barrier.
Scientific progress always relies on the development of new technologies. Humans excel at tool use, and we have always looked to nature for useful instruments. We see what is available to us and appropriate and modify it for different uses, as we have since we used bones as clubs. The natural world has always served as our toolbox. We chipped flint into crude arrowheads, smelted metals from rocks, and wore animal skins sewn with bone needles and plant twine. The technology that enabled the violation of the species barrier which genetic modification requires is also borrowed from nature's staggering bank of resources. They come from our most distant evolutionary cousins: bacteria.
In 1968, Hamilton Smith (then working in the Microbiology Department at Johns Hopkins University in Baltimore) isolated the first of a set of proteins that launched the era of genetic engineering, and for this he shared the 1978 Nobel Prize for Physiology or Medicine. These proteins are known as restriction enzymes and, put very simply, they act like DNA scissors. In nature, a bacteria's restriction enzymes cut their own double helix as a means of protection against the invasion of viruses. As a virus carries only its genetic code, and none of the machinery to replicate it, its purpose is to hijack the host cell to reproduce. The infected cell translates the virus's code and unwittingly makes new viruses, releasing them en masse until the cell bursts. Restriction enzymes are part of the arsenal to prevent that hijack by editing out the interloping DNA.
The ability to cut DNA is of profound use to geneticists, as restriction enzymes do not snip the code randomly. Instead, they only cut when they recognize a precise row of letters in the genetic code. There is a huge range of restriction enzymes, with some cutting at common sequences and others at very rare pieces of DNA. Imagine that working in this book: a restriction enzyme that makes a cut when it sees the word
cell
would shred this book into fragments, as if blasted with a shotgun. A restriction enzyme that cut when it recognized the word
jumentous
would chop the whole text neatly into just three pieces, as that uncommon word appears only twice.
This naturally occurring editing tool enabled scientists to treat DNA and genes as we now use word processing software: to cut, copy, and paste from one section to another. This paragraph began its life in another chapter, but with a couple of simple clicks, I transposed it here, and modified it to make sense. Similarly, the dragline silk gene began its life in a spider, and was transferred into the genome of a nascent goat, tweaked, and positioned so that it makes biological sense. Hundreds of restriction enzymes have now been isolated and characterized, and are cheap and readily available. Even better than merely moving text around, as DNA is a double helix made of two strands that mirror each other with complementary code, there is another useful trick these genome-editing tools can perform. Some simply cleave both strands of the DNA at the same point. These are called blunt ends, and any other blunt-ended DNA can readily stick to it, two ends glued together, like a blank domino. They are perfectly stable once linked, and have value to the gene engineer, as you can stick them in anywhere. But other restriction enzymes cut each strand a few letters apart, creating sticky ends, with one strand of DNA overhanging the other. That makes them an uneven domino, where you can only join to the end if you have the matching piece. A stretch of alien DNA that has the complementary sticky end can join with the host DNA, clicking neatly into place. This means inserts can be oriented in a particular direction, and other useful inserts added to make more complex genetic pathways, a run of dominos built by design.
In the lab almost all of these molecular biology experiments involve transferring minute quantities of colorless liquids from one tiny tube to another. The action of restriction enzymes on DNA is invisible to the naked eye, and we check success with a battery of proxy visualizations, such as measuring the mass of the cleaved or rejoined DNA fragments. It's often far from dramatic, and not easy to see the profoundly unnatural acts being perpetrated. Ultimately, though, the real test is to see whether and how these reconstructed codes work in cells and in organisms. Sometimes the effects might be gross and visible. But frequently, the impact of genetic modification might be subtle or cryptic, and so being able to detect where and when your experiment is working is a fine art.