Creation (23 page)

Afterword

New Languages

L
anguage evolves. Samuel Johnson noted in his famous dictionary that all languages “have a natural tendency to degeneration,” though throughout history terminal decline has been somehow miraculously avoided. That anxiety about the way languages change—along with a suggestion that languages once, at some point in the past, existed in perfect and inviolate form—has been expressed in every generation throughout history by brabbling malagrugs, but really only reflects the fact that words and their meanings constantly change over time. Cromulent words are added, mangled, misappropriated, and invented. Very occasionally, languages acquire new letters, too.
¹

Evolution settled on an alphabet of just four letters and twenty words, and just a single language. This alphabet and lexicon
²
has remained static since the beginning of life on Earth, a stable mechanism that is flexible enough to encourage evolution in a species but shields the individual from catastrophic changes to their genomes.

With the genetic code being the only language of life we know of, there is no possibility of importing letters or words from other life-forms; no direct analogy for the kind of borrowing and exchange we see between languages. However, genes and DNA—the words in our analogy, as opposed to the letters of the genetic code—can swap between species, particularly singled-celled species of bacteria and archaea. Yet they can also be transported harmlessly into more complex creatures when viruses integrate their genomes into a host. It is estimated that up to 8 percent of your DNA was once in the genome of a virus.

Just as we have difficulty in pinpointing the precise moment when a species comes into being, we cannot pinpoint exactly when English was born, or any of the myriad languages or dialects that are and have been spoken throughout human history. However,
Kelkaj lingvoj ne evoluas; kelkaj simple elpensiĝas
, as Esperanto speakers might say: some languages did not evolve; they were simply invented. Esperanto was a noble attempt to induce world peace by making a universal language; it survives a century after its creation with a few thousand speakers. In fact, something like nine hundred languages have been invented from scratch, including Klingon, as spoken by the angry fictional warriors of the
Star Trek
franchise and a few hundred devoted followers.

Our command of the language of DNA and its mechanics has brought us to the point where we no longer need be content with the four-billion-year-old alphabet, lexicon, and language of life. In the era of synthetic biology, we have begun the process of inventing new ones.

If you've ever had a cold sore, you've probably already used invented DNA letters. The universal letters, nucleobases, are merely chemicals.
A
for adenine is a collection of fifteen atoms: five carbon atoms, five nitrogens, and five hydrogens. They're arranged into a hexagon attached to a pentagon with a few molecular bobbles protruding. There is nothing inherently special about that arrangement, nor of the other bases that make up the genetic code. That doesn't mean that they are easy for us to build into that vital configuration, as John Sutherland's work demonstrated in part I (pp. 106–8), but those limitations are ours and not nature's. At some point in the distant past these chemicals acquired meaning—began to arrange themselves into a system from which information could be derived, stored, and handed down. The system arises from the shape of the molecules; how they link with one another and form a chain. We can now make our own chemicals, similar enough to these naturally occurring ones that they can be integrated into DNA. We're already using them in the fight against virus infections.

Typically, a virus will storm into a cell carrying its own genetic code but none of the mechanics to translate it. One of the reasons viruses are not typically classed as living is because they can only reproduce by using someone else's kit. So viruses hijack a living cell, insert their own code, and hope that it doesn't notice. This steganography by the virus uses the same language, so cells often don't spot the inveigled plan and they read it unwittingly. As a result, the host cell produces more viruses, which break out to infect more cells, often destroying the host in the process. Antiviral treatments include false letters that are similar enough to be incorporated next to their natural counterparts but conspicuous enough to disrupt any meaningful message. If you spot a massive interloping typo in the middle of a sent&ence, your brain is sophisticated enough to skip over it without misunderstanding. The cell is not so forgiving of the alien letters. They are designed so that the cell's translation mechanics see the new bases as unnatural, and won't skip over them. This is how many antiviral and cancer chemotherapy drugs work. These man-made alien bases are used as standard treatments for infections from HIV to herpes: when you dab cream onto your lips to soothe a cold sore you are probably applying acyclovir. The balm contains a molecule similar enough to the base
G
to go into the replicating virus code, but different enough to stop the sentence from continuing. The usefulness of this Scrabble bag of alien letters comes from the very fact that they are alien. They don't act as a readable code. Instead, their insensibility to cellular machinery gives them power to rudely thwart the virus's sole desire—to copy itself. Reproduction is halted, making it a very useful tool for fighting these invaders.

Naturally, the most interesting things we can do with invented DNA rely on our creating code that
can
be copied. If a code can't be copied, then it can't be passed on, and if it can't be translated, it can't have a function (beyond the terminating one described above). Many attempts have been made to make letters that can be snuck into DNA, and not only stay there, but get copied. Synthetic biologist Steve Benner (Westheimer Institute of Science and Technology) has led this effort and, in 2011, added two alien bases to the alphabet of genetics.

The double helix of DNA has two spines that twist into a spiral, so it has two grooves on the outside—twin spiraling slides. One is wider than the other, so they are called the major and minor grooves. Electrons whiz around the atoms down in the minor groove, just as they do in all molecules. Here they form an electronic pattern that acts like a chemical identifier, and they play an essential role in DNA replication. The protein that copies genetic code, DNA polymerase, has evolved to recognize this particular electronic signature, and is drawn in to begin its copying work. In order to trick the cell into incorporating unnatural bases into DNA, Steve Benner's tactic was to design new ones, called
Z
and
P
, that mimic the electron signature when integrated into the double helix, and DNA polymerase gets into the groove. We now have a DNA whose code is made up of an alphabet consisting of
A, T, C, G, Z,
and
P
. DNA polymerase happily does its natural thing, reading the code and copying it. As always, the copying process is not perfect, and there is an error rate equivalent to the accumulation of the mutations in DNA that drive evolution. Benner has added brand-new letters to the genetic code.

These new letters don't mean anything yet. This design and construction is a proof of principle—that extra letters can be added to DNA and that they will not disrupt the cell's normal behavior. The new techniques of biological engineering tend to rely on the existing mechanics of the cell to translate and enact the new designs of synthetic biologists. Naturally, alphabet letters don't have any inherent meaning in isolation, either. It's only when strung together into agreed-upon words and phrases that they stop being mere noise and transform into prose that can express love and render the complex understandable. If we were to simply add new letters to the English alphabet, say
Љ
and
Џ
(from Cyrillic), we would have no way of pronouncing them, and they would not have any meaning until a consensus was arrived at. However, this is not the only way to invent new languages.

Alien Code

This focus on the letters of the spiraling ladder of DNA is only one aspect of synthetic biology's attempts to reengineer the alphabet of life. DNA is a complex molecule, a polymer, meaning that it is assembled from repeating units. The code is hidden in the rungs of the ladder, but another major breakthrough in alternative, unnatural genetics has come not from swapping out or inventing new rungs, but the uprights of the ladder. These are made from a type of sugar called deoxyribose—the D in DNA (in RNA it is simply ribose)—which repeat and link up to form the spines of each strand. Since 2000, biologists have been creating alternative spines from a range of other sugars to produce several new genetic molecules: ANA (with arabinose), TNA (with threose), and four others including FANA and CeNA. These alien species are collectively known as xeno-nucleic acids, or XNAs. The letters of code remain the same, but the struts of the ladder are strange. In April 2012, again at the Laboratory of Molecular Biology in Cambridge, a team led by Philipp Holliger and Vitor Pinheiro built a system that for the first time enabled these foreign-language genes not only to replicate, but to evolve.

The genius of this experiment was not how the code was put together but the fact that it gets copied. DNA polymerase, the protein whose job is to copy a single strand of DNA to make it into a double, does so by reading one strand and picking up and stringing together the pieces to make that strand's mirror,
A
for
T, C
for
G,
and so on. DNA polymerase won't attach to anything other than DNA, understandably, as it has evolved over billions of years to do only that, and in nature there is nothing for it to act on but DNA. Proteins such as DNA polymerase are long and complicated, and their function is determined by their three-dimensional shape (which is determined by the order of their amino acids, which is determined by their genetic code). Because of this intricate 3-D conformation, they resist intelligent design: it is immensely difficult to redesign something so complex. Evolution is blind but clever; it designs by random experimentation and by selection of successful mutants. Pinheiro presided over a process of natural selection by creating a pool of polymerase proteins that were all fractionally mutated in key areas. By selecting mutants that could pick up XNA pieces instead of DNA, he forcefully evolved a polymerase that reads DNA, but lays down a mirror strand using XNA, as if the alien molecule was native. In this way, the brand-new, human-invented genetic molecule can carry the same message encoded in natural DNA. They effectively tricked the machinery of cellular cryptography into reading its natural language but copying it into an unnatural one. They built a tool that will translate a natural language into a made-up one, English into Klingon.

Yet that is only half the story. They can also translate back again. Pinheiro mutated and selected a protein that would do the opposite, translate from XNA back to DNA. That is a trickier trick, as no natural protein will do the job. After eight rounds of forced random mutation and selection, they had crafted something that did, which makes XNA a system bearing two hallmarks of life: information storage and heredity. Fidelity is important when copying, especially in genetics, but perfect fidelity is not evolution, it is stasis. Their process is faithful at around the 95 percent mark, which means the stored information can evolve.

This, if one cares about such naming conventions, marks the inception of a new branch of biology—synthetic genetics. Admittedly, this first study still relies on DNA as its template, but the team is already trying to cut it out of the loop. They have copied FANA to FANA and CeNA to CeNA, though it doesn't work quite as well as DNA yet.

The implications are weighty. Pinheiro and his colleagues have shown that genetic evolution is not limited to the natural code as we know it. There may well be uses for this gallimaufry of XNAs in the future, as they can behave like natural genetic parts even though they are not, and might not be treated as such by our immune systems, which have several billion years' worth of schooling in recognizing natural DNA- or RNA-based genetics. XNAs are more robust than DNA and RNA, both of which are prone to breakages and cuts by proteins called nucleases, whose role is to do just that. By being immune to slicing, XNAs have extraordinary therapeutic potential. Geneticist and origin-of-life scientist Jack Szostak has developed a class of molecule called an aptamer, which is strands of DNA or RNA designed to fold in such a way as to clasp onto a very specific target. As a potential therapy, this action has the ability to shut down a gene or inactivate a mutant protein. Currently, there is only one aptamer on the market, as a treatment for a degenerative eye disease. Yet it is vulnerable to being chopped up by nucleases patrolling for rogue bits of DNA, so the medicine has to be taken repeatedly. Theoretical at present, an equivalent XNA aptamer would be invisible to nuclease, a stealth weapon in the armory of medicine.

Altered Output

Both of these projects reinvent the code of genetics. Naturally, there is the output of that code to consider as well. Life is built by or of proteins, and with the advent of sophisticated molecular biology, proteins are now also subject to rewriting.

Proteins are built from the nose-to-tail joining of amino acids. At one end an amino acid will have an arrangement of atoms called an amine group (which is made up of a nitrogen atom and two hydrogens), and at the other a group that forms carbolic acid (which is a carbon atom, two oxygens, and a hydrogen). The genetic code in DNA spells out twenty amino acids, which are collected together in the process of protein manufacture and assembled by the cell.
³

Amino acid is a generic name for a set of molecules that are all quite similar. They vary only in what is attached to the middle section of the molecule, between the amine and the carbolic acid. The simplest amino acid is glycine, with only a single hydrogen atom as its unique side chain. At the other end of the scale is tryptophan, with a large double ring of carbons, hydrogens, and a nitrogen sprouting from the side. All types of variation in between make up life's lexicon. These side chains determine the behavior of the protein in which the amino acids are assembled. It's important to remember that there's no real limit to the number of amino acids that could exist, in theory, beyond the twenty that life actually uses.