Gene Drives

Named for their ability to “drive” themselves and nearby genes through populations over many generations, gene drives can spread even if they reduce the fitness of individual organisms.  They accomplish this feat by ensuring that they will be inherited by most – rather than only half – of offspring.  This inheritance advantage at the genetic level can offset costs to the organism.

In a landmark paper published in 2003, Austin Burt of Imperial College London first proposed that gene drives based on homing endonucleases might be used to alter or suppress wild populations. But the endonucleases available at the time couldn’t be used to drive alterations through most species.

Screen Shot 2015-03-10 at 12.20.35 PMWe recently outlined a technically feasible way to use CRISPR/Cas9, a genome editing technology we co-developed, to drive almost any genome alteration through sexually reproducing populations. These RNA-guided gene drives could let us spread most traits we know how to alter with Cas9. Given enough generations, nearly all organisms of the target population would have the same changes as those originally generated in the laboratory.

Gene drives could benefit human health by altering populations that currently spread diseases such as malaria, dengue, chikungunya, and Lyme so that they can no longer transmit the disease to humans.  They could improve the sustainability of agriculture by reducing the need for and toxicity of pesticides and herbicides.  Finally, they could aid ecological restoration by removing invasive species and bolstering the defenses of threatened organisms.



What is a gene drive?
It’s a stretch of DNA that is inherited more frequently than normal. In sexually reproducing organisms, most DNA sequences have a 50% chance of being inherited by each offspring. This is called “Mendelian inheritance”. Gene drives manage to rig the game so that they are inherited more frequently – up to 100% of the time.

Do they occur in nature?
Yes, many different kinds of gene drive occur frequently in nature. Almost every species has either an active drive or the broken remnants of one in its genome.

What is the advantage of using a gene drive?
When we engineer an organism, our alterations almost always harm its ability to reproduce in the wild. With very few exceptions, evolution is simply better at doing this than we are. But if we embed the same change within a gene drive, the inheritance advantage conferred by the drive can counterbalance the harm from our alteration, “driving” our new trait through a wild population over many generations. Given enough generations, nearly all organisms of the target species will have the same alteration as the first ones released.

Why would that be useful?
Right now, we have very few ways of addressing ecological problems because we can’t alter the traits of wild populations. We can’t stop mosquitoes from carrying diseases like malaria, dengue, yellow fever, or West Nile. If a weed has evolved resistance to an herbicide or a crop pest to an insecticide, we can’t do anything about it except switch to using new pesticides and herbicides. If an invasive species damages an ecosystem and causes native species to go extinct, we just don’t have many good options for controlling it.

How could gene drives solve these problems?
We might be able to alter the mosquitoes so they can’t carry disease or suppress their populations until the disease is permanently eradicated. Gene drives could directly reverse the many of the mutations conferring pesticide and herbicide resistance, supporting sustainable no-till agriculture and keeping us from having to switch to potentially more toxic pesticides and herbicides. Local populations of invasive species might be specifically suppressed or even eliminated by spreading traits that reduce the reproductive capability of each individual organism.

So why haven’t we done this before?
Austin Burt first proposed the idea of building gene drives based on cutting DNA more than ten years ago, but we didn’t have the molecular tools to cut and drive alterations in useful genes and species – especially not in an evolutionarily stable manner.

What changed?
In 2013, laboratories all over the world started using an enzyme from bacteria, called Cas9 or CRISPR, to alter the genomes of different species. Because Cas9 can recognize almost any DNA sequence using complementary RNA sequences, it’s very easy to use it to edit any gene. We realized that we could use Cas9 to make an “RNA-guided gene drive” that recognizes competing genes on the other chromosome and copies itself – and whichever genes it is driving – in their place.

RNA-guided gene drives could edit almost any gene in any population?
Not every gene, but most of the ones we’d want to.  It only works in sexually reproducing populations and may be more difficult in some species than in others.

That sounds pretty powerful. Should we be worried?
It’s entirely reasonable to be concerned about new and potentially powerful technologies. This one could be used to alter ecosystems, which we’re still learning about, so we’ll have to be very careful not to cause damage accidentally. At the same time, there are a lot of existing problems hurting people and ecosystems that we might be able to fix.

Could gene drives be used to alter human populations?
Not without taking many centuries. Gene drives take generations to spread, and our generations are quite long. Driving a trait would only increase the number of people carrying it by fourfold after a hundred years – and that assumes subsequent generations wouldn’t decide to remove it.

What about crops?
It would be quite difficult and highly impractical. Most crops and domesticated animals are the products of careful cross-breeding programs. Annual crops are grown from seeds obtained from central suppliers, while animals are often bred using artificial insemination guided by genetic records and screening. You can’t really drive a trait when we already control reproduction so carefully. Non-annual crops such as fruit and nut trees have long enough generation times that drives would take too long to spread. Agriculture would be much better served by controlling the weeds and insect pests rather than altering the crops.

Why did you decide to make this public before actually doing it?
If we’re right about this, it’s a powerful advance that could make the world a much better place, but only if we use it wisely. We think that’s most likely to happen if we make sure that people have a chance to learn what we’re thinking of well before we could actually put it in practice. That will let us collectively explore possible ways of developing and using this technological responsibly. Before going public, we consulted experts in a lot of different areas to be sure they agreed with our assessment.

Who did you check with and what did they think?
We consulted with a wide variety of people, from ecologists to molecular biologists to government regulators to security experts to representatives from environmental organizations. They had varying concerns about it, but everyone agreed it was better to tell everyone now so we can collectively start preparing to use this wisely.

How can we prepare to use this wisely?
It’s tremendously important to realize that the gene drive is just the vehicle. The effects will depend on the passengers – the particular genes or alterations that are driven through the population. So it doesn’t really make sense to ask whether we should use gene drives. Rather, we’ll have to evaluate whether it’s a good idea to consider driving this particular change through this particular population. Gene drives could prevent a great deal of human suffering and fix a lot of the damage we’ve already done to the environment, but each time we’ll need to carefully weigh the benefits of each proposed gene drive against the possible risks.

What else can we do?
We can be sure to develop safeguards as we develop the technology. For example, we outlined possible ways of controlling and reversing the effects of alterations driven through populations.

The effects of gene drives can be reversed?
Yes, genomic changes can be reversed by releasing a “reversal drive”. It should also be possible to protect a population from being affected by a specific gene drive using an “immunization drive”.

What other precautions could we take?
When we’re developing gene drives in the laboratory, we can make sure that there’s negligible risk that they will spread into wild populations by using appropriate containment. Molecular containment involves only building drives that cut and copy themselves using sequences that aren’t present in the wild populations. We can test them and optimize the drives using laboratory organisms that we’ve engineered to contain those sequences. We’ll also split up the components of the drive so key parts aren’t copied – they’ll have to be provided by the organism itself – and wild populations won’t have them. The other method is ecological containment, and it’s very simple: don’t build gene drives in geographic areas harboring wild populations. If we’re building gene drives in organisms native to Australia, we should do the work in the United States, and vice versa.

We suggest that gene drives with a substantial risk of spreading through wild populations – as opposed to those developed and tested in the laboratory with molecular or ecological containment – should only be constructed after notifying the public and with the approval of a scientific advisory board. More, laboratories should simultaneously make reversal drives capable of “undoing” the changes just in case something goes wrong.

Who will be able to make gene drives and how quickly?
Making a drive in a new species will probably take expert laboratories at least months to years. Just learning to edit the genomes of cells that will produce eggs or sperm can be quite difficult in some organisms. And while being able to cut the target with Cas9 is critical, there are many other factors that have to be considered and optimized to make a good gene drive – and those will differ with the species.

Learn more about it:

– Our manuscript in eLife comprehensively describes RNA-guided gene drives (easily navigated bioRxiv PDF).
– Our paper in Science analyzes potential concerns and recommends safeguards and regulatory changes.
– A history of gene drives by Fred Gould.
– An excellent book on gene drives and “selfish” genetic elements by Austin Burt and Robert Trivers.

– Our guest blog post at Scientific American focuses on capabilities and ethical considerations.
– The Wyss Institute press release.
NOVA has a well-written optimistic take on gene drives.
– For a more conservative view, see the article at the Boston Globe.
National Geographic focuses on the potential to improve the environment by controlling invasive species.
– The New York Times discusses the potential to control or eradicate malaria (while somehow failing to mention the lead and corresponding authors on the two relevant manuscripts).


Originally appeared on Sculpting Evolution here.
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