New Letters for Life’s DNA Alphabet Build on God’s Design

Can genetic engineers—by building a bacterium that speaks an unearthly tongue—reenact ancient evolution in the laboratory? Have they demonstrated that evolutionary abiogenesis—life from non-life—really happened?

Genetic engineering has taken a giant leap forward. Nature reports Floyd Romesberg’s Scripps Research Team has coaxed a bacterium to incorporate a bit of foreign language into its DNA. Though this foreign word means nothing to the bacterium as yet, writing a meaningful instruction using the two new letters is the next step. Once that hurdle is overcome, genetic engineers may rewire microbes to build biological products like pharmaceuticals and biofuels. In so doing they are capitalizing on God’s great biological design seen in all life on earth.

Life’s Information System

All living things use the same genetic alphabet and the same genetic language to store and transmit information in DNA. A few years ago researchers successfully designed several new “letters” (nucleobases) that fit into the DNA genetic alphabet. Now for the first time ever they have engineered a bacterium to accept a bit of genetic code containing foreign letters and to replicate them.

DNA utilizes just four “letters”—the nucleobases adenine (A), thymine (T), guanine (G), and cytosine (C)—to make three “letter” codons that stand for each of about twenty amino acids, the building blocks of all the proteins found in living things. These same four nucleobases also encode many regulatory switches in the genomes of organisms.

“Life on Earth in all its diversity is encoded by only two pairs of DNA bases, A-T and C-G, and what we've made is an organism that stably contains those two plus a third, unnatural pair of bases,” explains Romesberg, a leader in synthetic biology for fifteen years. “This shows that other solutions to storing information are possible and, of course, takes us closer to an expanded-DNA biology that will have many exciting applications—from new medicines to new kinds of nanotechnology.”

Fitting In

Life on earth is “biochemically uniform.”1 Therefore, genetic engineering until now has been limited to what could be built from the biochemical and biological materials and patterns found in living things. Getting an unnatural base pair to fit into a cell’s DNA and fool existing enzymes are the barriers Scripps researchers have now overcome.

The double helix of DNA consists of two long backbones of sugar molecules with nucleobases (A, T, G, C) attached. These strands align such that A always aligns with T and G with C. Thus when cells divide to make new cells, they unzip and replicate their DNA strands by building complementary strands on the template of existing strands. Enzymes called DNA polymerases build this DNA. Image by Zephyris, via Wikipedia Commons.

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The synthetic bases dNaM and d5SICS are transported across the cell membrane using a transporter protein borrowed from a microalga. They are incorporated into a DNA plasmid and replicated along with the rest of the bacteria’s genome. This diagram shows applications envisioned for technology utilizing alien nucleobases. On the left are synthetic possibilities in which a microbe carrying foreign code might manufacture useful substances. On the right are regulatory possibilities in which a microbe carrying the foreign code might be designed to switch other genes on and off. At the lower center is listed “genome evolution,” but though a genome containing these foreign words may change, all biological observations indicate there is no way for organisms to spontaneously evolve the information to become a new more complex kind of organism. Image by Ross Thyer and Jared Ellefson, via Nature.2

Now that genetic engineers have found a way to fool a cell into accepting synthetic nucleobases and building DNA with them, the next step will be to get a cell to follow the foreign DNA’s instructions, transcribing the foreign “word” into RNA and manufacturing a corresponding protein.

Researchers hope to use these cells like little factories with a host of potential applications. For instance, a bacterium might be engineered to produce a protein that specifically targets cancer cells. For many years genetic engineers have given us valuable drugs like Humulin manufactured in microbial factories following the instructions of human genes. This application could potentially extend that application to include pharmaceuticals and a host of other useful products incorporating amino acids not normally used in nature.

History-Making Hurdles

Synthetic biology has forced researchers to overcome a number of obstacles. For instance, DNA polymerase enzymes—the enzymes that build DNA—are not very forgiving of abnormal-looking genes. Scripps researchers placed their foreign letters at a location serviced by one of the more tolerant polymerase enzymes. Coming up with pairs of nucleobases that could geometrically fit into DNA strands, not hindering their unzipping and zipping, was the first step in this saga of synthetic biology and was achieved a few years ago.

The unnatural “alien” bases also have to be recognizable to the enzymes cells used to transcribe DNA instructions into RNA. This has also been accomplished in test tubes but not yet in cells. “These unnatural base pairs have worked beautifully in vitro,” says Denis Malyshev, lead author of the study published in Nature, “but the big challenge has been to get them working in the much more complex environment of a living cell.”

The twin keys to success in this history-making leap are described in the Malyshev et al.’s paper. They had to incorporate unnatural bases into a plasmid the bacterium could replicate using its cellular machinery. And they had to build a bacterium equipped to import unnatural bases as raw material for replication. The Scripps team synthesized a circular piece of DNA (a plasmid, a common way to insert extra genetic information into bacteria) containing the best-performing foreign base pair—d5SICS and dNaM. They used a gene borrowed from diatom microalgae to engineer a designer Escherichia coli equipped with a transporter protein to carry alien nucleobases—d5SICS and dNaM—across the cell membrane. Once inside the cell, the alien nucleobases were used by the cell's own DNA polymerase to build copies of the plasmid, incorporating the unnatural nucleobases where indicated.

Looking Ahead

Some have expressed concern that these organisms could be dangerous. Maleyshev says built-in safeguards prevent that possibility. “An important thing to note is that these two breakthroughs also provide control over the system,” Maleyshev says. “Our new bases can only get into the cell if we turn on the ‘base transporter’ protein. Without this transporter or when new bases are not provided, the cell will revert back to A, T, G, C, and the d5SICS and dNaM will disappear from the genome.”

Once the team learns how to make a meaningful “word” spelled with d5SICS and dNaM—perhaps by providing the cell with corresponding materials to make a codon containing the alien bases signifying an unnatural amino acid—practical applications of the technology should emerge. “What we have now is a living cell that literally stores increased genetic information,”3 Romesberg says. “In principle, we could encode new proteins made from new, unnatural amino acids—which would give us greater power than ever to tailor protein therapeutics and diagnostics and laboratory reagents to have desired functions.”

How far can this technology go? “A lot of times people will say you’ll make an organism completely out of your unnatural DNA,” answers Romesberg. “That’s just not going to happen, because there are too many things that recognize DNA. It’s too integrated into every facet of a cell’s life.”4 These designer cells can function only in the context of existing biological systems on which they depend.

Looking Back To An Evolutionary Past?

“The generation of a simple evolving system guided by these parameters in turn would have clear implications for the plausibility of proposed transitions from inanimate to animate matter at the origin of life,”5 commented Cambridge University molecular biologists James Attwater and Philipp Holliger. But has this research demonstrated anything supporting either abiogenesis or the notion that increasingly complex forms of life can evolve through natural processes? Indeed not!

Is the engineering of a bacterium that imports and copies novel nucleobases a picture of the ancient evolutionary process some scientists imagine spawned DNA-dependent life in the first place? Does this research open the door to show how evolutionary abiogenesis—life from non-life—could have happened? This research illustrates quite the contrary. These designer cells, as Romesberg says, store increased information. They do not create it.

Synthetic biology must operate within the context of the living systems God designed, utilizing the same patterns, information systems, biochemistry, enzymes, and cellular structures. Evolutionary biologists, unwilling to see the integrated biochemical uniformity of life is the result of a wise Creator’s design, attribute it to common descent from a hypothetical Last Universal Common Ancestor of all living things. Yet in so doing they propose that life evolved from non-living elements through natural processes—a clear violation of all experimental biology’s law of biogenesis. They further imagine that simpler living things can through natural processes acquire the information to evolve into more complex kinds of living things, even though this process has never been observed. Yet as Answers in Genesis molecular geneticist explains:

The genetic engineering of a foreign of pair “letters” compatible with DNA and of a bacterium able to accept and copy those letters beautifully illustrates creationist design principles. The bacterium was engineered using information provided to it from intelligent sources. A gene from microalgae built its membrane transporter. A pair of synthetic nucleobases synthetically integrated into the genes of a plasmid provided its new “word.” Intelligent scientists spent years copying, tweaking, and imitating God’s designs in order to achieve all this. The bacterium never acquired information on its own, and it never became anything but a variation of the same kind of living organism it always was. And nothing non-alive spontaneously turned into a living organism or even into the information contained in a gene.

Intelligent designers can invent new languages. Computer engineers do that. An intelligently designed computer algorithm can do that. Even a sci-fi geek can do that, as evidenced by Trekkies who speak Klingon. If scientists were to invent a new genetic code and then manage to create synthetic analogues for all of life’s processes, would that demonstrate abiogenesis? No it would not, because information would still be supplied, not randomly have come into existence on its own as molecules-to-man evolution would demand.

And if we want to understand the molecular origins of life we must look to the historical record supplied by the intelligent Creator of all life. The history of our origins in God’s Word is consistent with what we observe in the study of living things. Molecules-to-man evolution simply is not. It will be interesting to see what technological applications eventually spring from responsible research that capitalizes on God’s great designs for life.