June 5, 2018
Programmed for safety: How Synvivia is commercializing biocontainment technology
Gabriel Lopez is the founder and CEO of Synvivia, a startup in the San Francisco Bay Area that makes ON-OFF switches for engineered organisms. During his Ph.D. at UC Berkeley, Gabriel developed a genetically encoded biosafety strategy based on ligand-dependent essential genes. This research laid the groundwork for Synvivia’s technology today.
The son of a biologist and an artist, Gabriel’s demeanor is low-key. As our conversation progressed, I found that he’s also fun and colorful, sharp and engaging. His candid comments like, “I think humanity is great! I don’t want it to go away like the dinosaurs,” made us burst into laughter. At the same time, there was something revelatory about hearing him call out the obvious.
We talked about Synvivia’s technology, its potential benefits, and why everyone developing engineered organisms should check it out. This interview has been edited and condensed for clarity.
Rodalyn Guinto: Tell us about Synvivia and what you do.
Gabriel Lopez: Synvivia’s mission is to provide ultra-robust biocontainment for genetically engineered organisms so that synthetic biology can be used outside of the lab. By addressing the potential safety and containment issues associated with certain engineered organisms, we hope to expand the use of engineered organisms that provide solutions to disease, energy, food, and materials.
Synvivia is pursuing this goal by developing ON-OFF switches for genetically engineered organisms. These protein switches respond to small molecule signals. By installing these switches into the genome, we can control the entire organism with small molecules. We’re using this technology to develop the first commercially available genetically encoded biocontainment system for engineered organisms. Such control and containment measures are critical for synthetic biology to move out of the lab and into the world.
Guinto: Why is biocontainment of engineered organisms important?
Lopez: Synthetic biology offers new solutions to many therapeutic, environmental, and industrial challenges. For this reason, I think we’re seeing more attempts to move engineered organisms out of the lab and into the world. But this comes along with some risks. Some people are concerned with the environmental consequences, while others fret about health risks. Genetically encoded biocontainment provides a solution to address these concerns.
If we’re going to release engineered organisms into the environment, they’ll typically satisfy three criteria. First, they must be able to survive in that environment. Active organisms generally yield more robust biological outputs. Second, they must be able to replicate in that environment. Self-replication is key to taking advantage of the scalability of biology. Third, they must have some impact on the environment. If they don’t do anything, why release them in the first place?
If our genetically engineered organism works when and where it’s supposed to, then we’re in the clear. But, things don’t always go according to plan. Imagine a genetically engineered organism that remodels the soil microbiome to boost crop yields. Such a technology would be great if you live in an impoverished nation with poor soil quality because it might help you feed your family. However, if an endangered ecosystem sits right next door, an engineered organism that can colonize and alter such a delicate environment could have undesirable consequences.
Another benefit of biocontainment is that it can reduce business risk. There are penalties each time an engineered organism malfunctions, escapes, or causes harm. These penalties come in the form of customer lawsuits, orders from regulatory bodies, damage to reputation, or losses in stock value. CAR-T cell therapies have had some very informative difficulties that illustrate the business impacts of malfunctioning engineered organisms. Genetically encoded biosafety measures address expensive safety risks and increase the expected return on investment.
Guinto: Who might be interested in this technology?
Lopez: Hopefully everybody. Our technology is to biology as transistors are to electronics. If you look at how transistors changed technology, they’d have to be one of the most important inventions of the century. Our phones, computers, and modern way of life wouldn’t be possible without the transistor. In the same way that transistors transformed modern electronics, I think biological switches will have a similar impact on synthetic biology.
Right now, biological switches are in their infancy, but they can already enable whole new classes of valuable products like dynamically controlled fermentation strains, metabolite sensor-selector cells, and environmental chemical sensors. I think there’s one application in particular that stands out from the rest: biocontainment.
Biology can grow, spread, and alter its environment. But the very attributes that make synthetic biology so powerful also present some serious risks. In order to avoid the synthetic biology equivalent of an oil spill, biocontainment is critical.
Synvivia’s ON-OFF switches bring biocontainment, biosecurity, and biosafety to engineered organisms. This technology will allow the safe use of engineered organisms, especially when they’re being released into the environment or used in a patient.
By improving safety and control, we might also be able to increase the potency of engineered organisms. This would be really helpful in the development of live biotherapeutics, which often present tough choices between safety and efficacy. We’ve seen this with live vaccines, oncolytic viruses, and cell therapies like CAR-T. The right switches should solve this challenge, allowing the potency of live biotherapeutics to be safely increased, without attenuating the components that make them effective to begin with.
Guinto: What are the advantages of this technology?
Lopez: I could probably write you a novel about all of the advantages we offer. The short version is that our technology combines super easy setup with engineering flexibility to achieve ultra-robust containment. This makes our technology a very practical solution for real-world problems.
One of the key advantages of our technology is modularity. This makes installing our technology easy. We can boot up our tech with a few quick genome edits. Modularity also means that our tech should work with pretty much any organism you want. So far we’ve found our technology to be compatible between different species, performing very well in different microbes useful for industrial, therapeutic, and agricultural applications. This is in contrast to other strategies that require you to re-code the entire organism or fine-tune complex transcriptional circuits. Good luck using those strategies in plants and animals. Is it possible? Probably. But they don’t look like easy or practical solutions when there are faster, cheaper, and better options. I could be wrong, but I guess we’ll let the market decide.
Another key advantage of our technology is flexibility in terms of control molecules. You’re not stuck with specific molecules like transcriptional effectors, steroids, or amino acids. As long as they can cross the membrane, we can use pretty much any molecule that we want to control cells. We’ve had awesome results on this front too. We’ve engineered switches that respond to a variety of different molecules, including GRAS [Generally Recognized As Safe] molecules like vanillin and FDA approved drugs. Using a GRAS molecule should simplify the regulatory approval process compared to using a new molecule with no safety history.
Guinto: How well does this technology perform outside of the lab?
Lopez: This is something that plenty of people are thinking about because I get this question a lot. We’ve found that our technology works well in complex biological conditions like blood, non-sterile soil, and non-sterile feces. This tells us that there’s nothing in those complex soups of biomolecules that interfere with our technology. This means engineered organisms will stay safe and contained in conditions found outside of the lab during real world use.
Guinto: What are the weaknesses of small molecule dependency as a biocontainment strategy?
Lopez: There are two questions inside of that, both related to how the system might break. The first is, how might evolution break this? The second is, how might a biohacker break this?
So let’s start off with the evolutionary one because that’s easier to solve. If we put one ON-OFF switch into a cell, then evolution will break it at a measurable frequency. We call this the “escape frequency.” This will happen maybe 1 in every 1 x 108 cells or so. But what’s really cool is we can add a second switch in for redundancy. When we do this, escape frequency drops multiplicatively. So if we have a 1 x 10-8 times 1 x 10-8, now the escape frequency is 1 x 10-16. By combining 3 switches, we get a theoretical escape frequency of 1 x 10-24. Add a fourth and we get to the point where even if you had every single cell in the world, you wouldn’t get an escape. (There are about 1028 to 1032 cells on Earth.)
Guinto: Alright, and what about the biohacker?
Lopez: That’s a much more difficult problem to solve. With today’s sequencing technologies, anyone can see what modifications were made in an organism and hack around them. We have to ask what the biohackers and biopirates are hoping to accomplish. Are they trying to steal the organism and avoid royalties? Or maybe they just care about a pathway that could be PCRed out.
While I doubt there’s a perfect solution, I think we can at least slow people down. We probably don’t even need to lock people out of a strain completely. In many cases, a crippled organism is useless and would take just as much effort to optimize as engineering it from scratch. This might actually be more effective than a “perfect” containment system, because it lures a hacker into wasting their time and resources on a futile endeavor.
Guinto: When will this technology be commercially available?
Lopez: The short answer is now. The long answer is that it depends on your application.
Because our tech works so well in different contexts, there are a ton of potential applications we could dive into. We have some compelling data on a variety of other applications ranging from metabolic engineering to therapeutics. Picking the killer app is one of those good challenges we face. Right now we’re laser-focused on the biocontainment aspect of our technology because it solves a really big problem in synthetic biology in a simple and effective manner.
Guinto: What would you like others to know more about synthetic biology?
Lopez: When I think about the power of biology, I think about the Great Oxygenation Event. Four billion years ago, Earth had no oxygen. Then cyanobacteria showed up. This new microscopic organism evolved an oxygenic photosynthesis and managed to fill every single ocean, changing the chemistry of the entire planet. However, the mass extinction that resulted should serve as a warning. The unintended consequences of new biology function can be extreme. If we create something that makes Earth less suitable for humanity, we’re going to be in a world of hurt. We need to think very carefully about these risks.