‘Daisy drives’ will let communities alter wild organisms in local ecosystems
Who should decide whether, when, and how to alter the environment? Even when there is consensus on the global benefit — such as eradicating a deadly disease — it’s a hard question to answer, made even more difficult when the technologies being considered will necessarily affect very large areas in many different nations.
One such technology is “gene drive,” a method of altering the traits of wild organisms over many generations. Gene drive could prevent diseases that are spread by mosquitoes and ticks, promote sustainable agriculture by replacing toxic pesticides, and save endangered species and native ecosystems by precisely removing invasive species. Drive systems based on CRISPR — a programmable molecular scalpel that can cut and edit any DNA sequence — have now been demonstrated in four species.
However, this kind of gene drive system can spread indefinitely, potentially affecting every population of the target species throughout the world. It’s unclear how such “global” drives can be safely tested, much less whether nations can agree to use them.
Here at the MIT Media Lab’s Sculpting Evolution research group, we devised a new form of drive system called a “daisy drive” that can only affect local environments. The trick was to teach DNA to count.
Global drive systems have everything they need to spread indefinitely. A single piece of DNA encodes the desired alteration, the CRISPR system, and the instructions telling it where to cut. 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 this alteration, as will their offspring, and so on until the drive system has spread through most or all of the population.
In daisy drive systems, however, the CRISPR components are split up and scattered throughout the genome so that none of them can “drive” the alteration 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. But no one alteration can sustain the change on its own.
Element C doesn’t drive, so its abundance is limited by the number of daisy drive organisms released. And since engineered changes made by humans are typically costly to the organism because they’re designed to do something other than help it reproduce, 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 like 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. Once shown to be effective, the same changes could spread using a more permanent global drive once there is widespread agreement. Adversely, if the daisy drive alteration proves ineffective or problematic for any reason, it can be left to “die out,” allowing the population to return to its original state, or undone more rapidly with a daisy reversal drive.
We joined up with researchers at Harvard University to figure out 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. We feel strongly that closed-door science is 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 — including proposed safeguards — well before we do it.
The major risk posed by a daisy drive is that a rare event will move DNA encoding a drive component on one chromosome so that it is adjacent to a drive element on a different chromosome, thereby undoing the separation that prevents indefinite spread. 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 now have enough diverse components to build what should be stable five-element drive systems.
Of course, with drive systems, “should” isn’t good enough. John Min, a graduate student in Sculpting Evolution, is now building daisy drive systems in nematode worms, which reproduce quickly and can be grown in the laboratory in the billions. The idea is to observe the evolution of drive systems in extremely large populations — ideally, at least as many as would be altered if released into the wild — in order to confirm that drive systems are stable and will not evolve in unexpected ways.
We hope that daisy drives will simplify decision-making concerning the possible alteration of wild organisms in order to address some of the world’s most critical disease and ecologic threats. Our goal is to promote responsible use and to give local communities the autonomy to decide how to solve their own ecological problems.
Kevin Esvelt leads the Sculpting Evolution group, which invents new ways to study and influence the evolution of ecosystems. By carefully developing and testing these methods with openness and humility, the group seeks to address difficult ecological problems for the benefit of humanity and the natural world.
Prior to joining the Media Lab, Esvelt wove many different areas of science into novel approaches to ecological engineering. He invented phage-assisted continuous evolution (PACE), a synthetic microbial ecosystem for rapidly evolving biomolecules, in the laboratory of David R. Liu at Harvard. At the Wyss Institute, he worked with George Church to develop the CRISPR system for genome engineering and regulation and began exploring the use of bacteriophages and conjugation to engineer microbial ecosystems.
Esvelt first described how CRISPR gene drives could be used to alter the traits of wild populations in an evolutionarily stable manner. By emphasizing universal safeguards and early transparency, he has worked to ensure that community discussions always precede and guide the development of technologies that will impact the shared environment.