Scientists found ways to expand the genetic alphabet beyond the simple genetic A, C, T, and G some time ago. The question for those obsessed with application rather than discovery is this: How can we make new amino acids work for us? How will we capitalize on new genetics?
California-based startup Synthorx wants to use the new acids to make new kinds of drugs to treat diseases and symptoms. With the addition of the X and Y to their toolbelt, the company hopes to start creating genetically modified bacteria in order to produce a new array of potential medicines.
Inverse spoke to Synthorx CEO Court Turner about the Amino Acid gold rush and synthetic solutions to intractable organic problems.
So, expanding the genetic alphabet. Where did it all start?
Floyd Romesburg’s lab at the Scripps Research Institute, here in La Jolla near San Diego. He’s been working on this for the last 15 years. His goal was first to answer the question: Was A, T, C and G — the natural DNA — all that could be replicated and translated by nature, or was there some way you can add to the alphabet and expand it? And so he spent the last 15 years developing [our new base pair] X and Y. Last year, he published in Nature how he was able to get X and Y to incorporate into a bacterial cell and be replicated and treated just like natural DNA.
The body is like a hard drive. Your DNA and genes are on the hard drive, and you pull that information out, and — in the context of biology — you’re making proteins, which do a lot of the work inside and outside of cells. The goal was, if you could come up with an expanded genetic alphabet, could you in turn generate novel proteins with novel or improved functions. The applications would be in therapeutics or technology.
It turns out after 15 years of [Romesburg’s] work and an additional year of work within Synthorx, the answer is yes, the genetic alphabet is actually useful for producing novel proteins.
What is the company doing right now. How is it expanding on the previous synthetic biology research and building on it?
We’re going to be able to take the work thus far and ask specific questions around certain therapeutic stories. Right now, there are a number of drugs out there in the biologic space for cancer therapeutics or other indications. And our question we now want to answer is: Can we develop novel proteins that would improve upon certain therapeutic applications? For the most part, all of the biologic drugs that are out there are made with natural amino acids. They’re natural proteins. We want to find out if we can improve upon the function of those by adding unnatural or novel amino acids into it. Our goal is make better antibiotics and better therapeutics as a result of the expanded genetic alphabet.
How are the scientists in the lab accomplishing this seemingly incredibly feat?
One of the amazing things about the technology around X and Y — and probably why it took 15 years for Dr. Romesburg to get there — is that in the context of the other nucleotides [A, T, C and G], we can use normal laboratory techniques to do our experiments. That’s a major upside of the technology — you don’t have to create all these new techniques to manipulate X and Y. You can use standard molecular biology. So we were able go after the experiments in the same way we would with natural DNA, RNA, and proteins. And we were trying to figure out whether the cell’s machinery — all of the protein and organelles inside the cell — would treat X and Y the same.
Amino acids inside of a protein are coded by what’s called codons — these triplets of base pairs in DNA. So in order for us to do this, we used novel codons, which contain an X or a Y in that triplet. We screened through about a hundred of these novel codons, to see if they were treated like natural codons, and would incorporate these novel amino acids.
There are 216 total codons that we have access to in our company, whereas nature has 64. So we went through and tested an initial 96, and found many novel codons that we can use to incorporate novel amino acids for proteins. We did that hundreds of times to confirm initial studies, and we came out with the ability to use our novel codons to make proteins of novel function and composition that didn’t exist in nature.
When it comes to applications, you’ve mentioned novel drugs. Are there specific diseases or disorders you guys have in mind to target and treat?
Antibiotics, for the most part, came from natural sources. In nature, bacteria are constantly fighting this war against each other, making their own antibiotics to try and kill the bacteria around them. So what we can do is generate peptides or drugs that look much like natural compounds. The antibiotics space — or the anti-infections space, if you’re talking about antivirals or antifungals — our technology is uniquely positioned to create new drugs in that space.
I think there’s also potential in the biologics space, which right now is focused on cancer therapeutics. I think we’ll have a great opportunity to impact and improve upon a number of therapeutics in the cancer space, because we can come up with novel large and small proteins to treat cancers.
Outside of that there’s a way to control nucleotides to put them in certain sequences. You can make things for novel barcodes, for things like anti-counterfeiting purposes. We can come up with a barcode that has millions of DNA nucleotides in a sequence, and then spray it on guns, or money — whatever high-value assets you want to label. And that DNA is very stable for many years. If you need to get that information, you can take a swab, and then use lab techniques to find out what the barcode is and where it came from. This also has applications in microchip design and nanowires, and other miniature applications.
Where is the company now in comparison to its goals? What else does Synthorx need to accomplish in the next few years to be where it needs to be?
We need to expand the team. We have eight full-time employees right now. We spent a lot of time getting the “base-expression system” working. Now that we have that, we have the team working on developing drugs, so we have to bring in the expertise to help with that. And certainly we want to soon be in a position to bring the drugs into the clinics and start human testing. At that point, I think you’d really be able to say for drug discovery applications that we’ve taken the technology from academia and expanded it to a full protein expression system, and now we’re at the new phase where to apply it to drug discovery.
The last thing I want to mention is the worry among people who read about synthetic biology that scientists are going to create a mutant organism that will get out in nature and take over the world. The good thing about Dr. Romesburg’s technology is that if it’s in a live cell, we have to feed the cell unnatural triphosphates — the chemical compounds it needs to replicate the DNA. If you don’t feed the cells this ingredient, they won’t live or they’ll revert back to their natural, wild-type state. So if the cells get out of the lab, there’s no chance of them to live in nature, because they won’t have access to this ingredient. There’s obviously ethical and safety questions that come with this field, but I think with our technology, we have the safety mechanisms in place.