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In every 8th grade science class, you learn the five nucleic acids that make up the base pairs in DNA and RNA: A,C,T,G, and U. These and these alone, we’re taught, are the building blocks of life. Not anymore.
Researchers have astoundingly created two new completely, unnatural base pairs and have integrated them into a bacterial genetic code, creating semisynthetic life that could one day be used to create new medicines. For the first time, those base pairs, which are completely different from adenine, cytosine, thymine, guanine, and uracil, have been bonded together and inserted into a living bacteria (in this case, E. coli), where it is naturally replicated as if it were any other genetic material.
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“We can use the processes of evolution to evolve proteins that do specific things and make them make better drugs,” Floyd Romesberg, the researcher who has spent more than a decade on the project, told me in an interview. “You can put whatever chemical structure you want in to create completely abiotic proteins that are not found in nature at all.” Beyond new drugs, synthetic life can be used to create new materials useful for nanotechnology and, eventually genetic engineering.
The finding, published in Nature, is the result of 14 years of research at The Scripps Research Institute and fundamentally changes what we know about what makes up life. It represents a new way of doing genetic engineering, fosters in a new understanding of what makes DNA, and will, if everything goes according to plan, allow researchers to create proteins and, by extension, traits that have never before been seen in nature.
Creating new nucleotides (X & Y) opens the door to creating a potentially unlimited number of new synthetic proteins. Image: Synthorx
In a naturally-occurring organism, A,C,T,G, and U are used by DNA and RNA to code for amino acids, which make up proteins, which perform most functions that living things do. Right now, DNA and RNA can only code for roughly 500 amino acids, based on the number of three-letter combinations of those nucleic acids. By creating completely new base pairs, that goes out the window.
“If we add these to existing nucleic acids, we might get exciting or new functions we can’t predict,” Ross Thyer, a University of Texas-Austin researcher who is familiar with but not involved in the research, told me.
In an accompanying article about the finding, Thyer wrote that this could “open up a new vista in which human engineering can leap chasms previously unfathomable to evolution,” which is one of the reasons why DARPA is working on similar research. Romesberg told me that the most immediate application of the research will be to try to create unique new proteins that can be used to make new drugs.
Scientists will eventually be able to essentially code for a bacteria to create a protein that can solve for a certain problem—bind to a certain receptor, for example—and the bacteria, using an unnatural base pair, might be able to make one that works better than anything we’ve found in nature. That means that, instead of trying to create something in the lab, the bacteria (or whatever other living organism) will do it as part of its normal cell function. Protein-based therapies are being tested to treat diabetes and cancer and are being used to keep the body from rejecting organ transplants.
“The cell sorts through literally millions of possible solutions to know what works best. We don’t need to know the answer. Medicinal chemists take decades to create this things,” he said. “If we can put those sorts of molecules into a biological process, that goes from being decades to being weeks.”
That’s because, using the basic principles of evolution, researchers should, in theory, be able to pit cells against some sort of task, use unnatural base pairs to code for unnatural amino acids which will code for unnatural proteins, and see what survives.
While Romesberg has created “semisynthetic” or “augmented” life, there are still, as you’d imagine, some hurdles to get over. The base pair can now be inserted anywhere in the bacteria’s genetic code (that’s a new development, one not noted in the Nature paper), and it will be replicated naturally by the bacteria. That’s huge, but the next step is to see if RNA in the cell can actually read what the DNA is coding for. From there, new amino acids and new proteins will be produced. Romesberg says that, in a test tube, the process works—now it’s time to try it in a living cell.
The researcher says that the fact that this works suggests that there’s nothing terribly unique about A,C,T,G, and U—a question that biologists have been asking since James Watson and Francis Crick discovered the structure of DNA. Instead, the building blocks of life are a chemistry problem that can be attacked from different ways.
In this instance, the base pairs (d5SICS and dNaM—which don’t quite have a snappy ring to them) have a completely different structure than the traditional base pairs and bond together because they are both hydrophobic (traditional base pairs use hydrogen bonds to stay together). But it doesn’t appear to matter—they work just fine in an organism.
“We stepped completely outside the paradigm. The [new base pair’s] mechanism of pairing is very different. Their structure is completely different. It shows that everything you need to store genetic information comes down to using basic chemical principles,” he said. “The natural letters are not the only solution.”
Should we be worried about tinkering with the very building blocks of life? Maybe, but not quite yet, according to Thyer.
“Attempts to expand the genetic alphabet bravely question the idea of the universal nature of DNA and potentially draw criticism about the wisdom of tinkering with it,” he writes. “Genetics has inexorably yielded a mechanism for greater biological diversity, and thus potentially for building a better biological future.”
