Daisy Drive Systems

Who should decide whether, when, and how to alter the environment? It's a hard question, especially when the decision will impact people in many different communities or nations.

Daisy drive systems enable each community to make decisions about its own shared environments by altering only those wild organisms within the local area. Theoretically, certain forms of daisy drive might even allow us to restore populations to their original genetic state. Preprints describing daisy-chain, daisyfield, and daisy quorum drives for population restoration are available on bioRxiv.

Daisy-chain gene drives

The problem with current CRISPR-based gene drive systems is that they can spread indefinitely. That means releasing a handful of organisms could eventually affect every population of the target species throughout the world. It's unclear how these systems can be safely tested, much less whether nations will ever agree to use them.

To return power to the hands of local communities, we devised two kinds of daisy drive systems that can only affect local environments. The trick was to teach DNA to count.

Standard drive systems spread indefinitely because they carry everything they need to copy themselves. A single piece of DNA encodes the desired alteration, the CRISPR system, and instructions to cut the original DNA sequence. In cells that produce sperm or eggs, CRISPR cuts the original version, causing the drive construct to be copied in its place. All of the organism's offspring will inherit a copy, editing will happen again in the offspring, and the process repeats until the drive system has spread through most or all of the population.

In daisy-chain drive systems, the CRISPR components are split up and scattered throughout the genome so that none of them can be copied on its own. Though physically separated, they're functionally arranged in a linear daisy-chain: element C causes element B to drive, and element B causes element A to drive.

Element C doesn't drive, so its abundance is limited by the number of daisy drive organisms released. And since changes made by humans are costly to the organism, natural selection will gradually eliminate C from the population. That means B will initially increase in abundance, then decline and vanish. In turn, A will increase even more rapidly, but eventually will run out of B and disappear.

In other words, the elements of a daisy drive system are similar to booster stages of a genetic rocket: those at the base of the daisy-chain help lift the payload until they run out of fuel and are successively lost. Adding more links to the daisy chain will spread the payload to more organisms. Releasing a daisy drive organism with a five-element chain (E→D→C→B→A) is hundreds of times more effective than releasing one with only element A.

Best of all, daisy drive systems can do anything a global drive system can do - including directly suppressing target populations - and use the same mechanism. That means communities could decide to use daisy drives to solve local problems, which could build and once they're shown to be changes that could later be spread using a global drive.

We joined up with researchers at Harvard University to figure out what exactly how powerful daisy drives would be. Charleston Noble, a graduate student who works with Martin Nowak and George Church, created detailed models using assumptions based on the efficiency of current gene drive systems.

The research hasn't yet been published in a peer-reviewed journal, and only two-element daisy drive systems, called “split drives,” have been previously demonstrated. But we're adamant that gene drive research must be open and responsive, which means telling people about the idea before running experiments. Closed-door science is wildly inappropriate when a laboratory accident could directly affect people outside the lab. We first described CRISPR-based gene drive before performing experiments to set this example, and we will always detail what we're planning to do – including proposed safeguards – well before we do it, currently as bioRxiv preprints with pre-registered planned experiments.

Are there any risks posed by daisy drive systems?
The major risk is that a rare event will move DNA encoding a drive component from one element to another, thereby creating a 'daisy necklace' capable of global drive. Since this kind of recombination depends on similarity of DNA sequences, we designed dozens of variants of the CRISPR components to come up with a set that aren't similar to one another, then worked with George Church's lab at Harvard to identify those that still work well enough to use. We should now have enough diverse components to build stable 6-element drive systems.

Of course, with drive systems, 'should' isn't good enough. John Min, a graduate student in Sculpting Evolution, is now working to build daisy drive systems in nematode worms, which reproduce quickly and can be grown in the laboratory in the billions. The idea is to observe their evolution in extremely large populations – ideally, at least as many organisms as would be altered if a daisy drive system were to be released into the wild - in order to confirm that they are stable enough to consider deploying.

What are other possible solutions?
Another option is to use a form of daisy drive that doesn't have any homology at all. Instead of a daisy-chain of linked elements (C→B→A), imagine scattering dozens of B elements - a 'daisyfield' - all over the genome. As long as at least one of these is present, element A will be copied, but every generation of mating with wild-type halves the number of daisy elements. This simple generational clock serves to limit spread.

How can we stop engineered genes from moving into nearby populations?
Just because a daisy drive can't spread forever doesn't mean that normal gene flow won't move its components, possibly into communities that haven't consented. This is a hard problem, but we've found a way to ensure that any such genes will be rapidly weeded out: the daisy quorum drive.

The idea is to use daisy drive to swap two genes that are required for the organism to live. As long as a daisy drive element is present, both will be inherited. But once they've all been lost, only half of the offspring of organisms with both swapped and normal versions will inherit one of each; the others will die. That means it's good for swapped versions to mate with swapped versions, and normal with normal, but mixing is penalized. Populations will consequently be one or the other, helping to confine changes to consenting communities.

What about reversing changes?
Perhaps most excitingly, daisy quorum systems can theoretically be turned in daisy restoration drives capable of restoring populations to their original genetic state.

We hope that daisy drives will simplify decision-making and promote responsible use by allowing local communities to decide how to solve their own ecological problems.