by Jessalyn Ubellacker
figure by Jovana Andrejevic

Between September 1999 and June 2000, the first human genome was sequenced. Since then, scientists have learned not only to read the human genome, but also to manipulate it, offering unprecedented opportunities to improve human health through genetic alterations. One example of this is gene drive technology, which circumvents classical inheritance patterns to ‘drive’ the presence of particular genes throughout a population. In the following article, we will explore the essence of gene drive technology and delve into a multitude of its potential applications.

How does normal gene inheritance work?

Have you ever wondered how likely it is that you will inherit a certain trait from one of your parents? These traits are determined by specific chunks of DNA known as genes, that are connected together to make up the 23 chromosomes in humans. Every person carries 2 copies of most genes, one inherited from each parent, and the combination of genes you inherit determines the traits that you will ultimately have – such as your height or the color of your hair.

As an example, let’s consider the inheritance of red-green colorblindness, the genes for which are located on the X chromosome. Males have 1 X chromosome and 1 Y chromosome, and all males inherit their single X chromosome from their mothers. If the mother is a carrier for red-green colorblindness (which means that she “carries” one normal vision gene and one defective vision gene), then her son will have a 50% chance of inheriting the defective gene and a 50% chance of inheriting the normal one. As such, he will have a 50% chance of exhibiting red-green colorblindness. Normal inheritance, then, is a numbers game – it is a matter of probability and chance. Gene drives, in contrast, change the rules of the game. Rather than leaving inheritance simply up to chance, gene drives tip the probability in favor of a particular gene to ‘drive’ its expression throughout a particular population.

How do gene drives work?

Gene drive technology relies on the use of CRISPR/Cas9, which allows for genes to be deleted, modified, or inserted in such a way that the altered gene is always inherited in the offspring. The CRISPR system has two primary components: the Cas9 protein and a molecule called a guide RNA. The guide RNA directs Cas9 to a specific gene, where Cas9 can then cut DNA at this location (Figure 1, top). Once the DNA is cut, the CRISPR system directs the cell to repair the broken DNA, as by inserting a new gene that we want to “drive” throughout the population. In this way, the gene drive becomes incorporated into the DNA of the target organism.

Figure 1. CRISPR/Cas9-mediated gene drive technology Top: CRISPR/Cas9 uses a targeted guide RNA to introduce a gene that encodes resistance to the malaria parasite in mosquitos. Bottom: The drive gene gets passed onto the offspring, who will also inherit one normal gene from their other parent. The drive gene cuts into the normal gene, and the latter will repair itself by copying over the gene drive template. The organism now has two copies of the gene drive alleles that then have a 100% chance of getting passed onto the offspring.

As an example, let’s consider how gene drives might be applied to curb the spread of malaria, a disease passed to humans by mosquitos infected with a malarial parasite. To reduce the number of infected mosquitos, scientists have developed a gene drive that carries a malarial resistance gene, along with the genetic information for both Cas9 and a guide RNA. When a mosquito embryo is infected with this gene drive, the guide RNA will direct Cas9 to a specific spot in the genome where Cas9 will make a cut, creating a gap in the DNA that the cell must repair. In the repair process, the CRISPR system can direct the cell to use the gene drive DNA as a template, thereby inserting the gene drive DNA into the mosquito genome. Because mosquitos, like humans, have 2 copies of their genetic material (one copy from each parent), the gene drive will be inserted twice, once at each of the two identical spots of the genome targeted by the guide RNA.

When this gene drive mosquito mates with a normal, or wild type, mosquito, its progeny will inherit one gene drive and one normal piece of DNA lacking the gene drive, as is dictated by classical inheritance patterns. The key here, though, is that this single gene drive copy not only carries the malarial resistance gene, but ALSO the DNA for Cas9 and the guide RNA. In the progeny, Cas9 and the guide RNA will function just as they did in its gene drive parent, cutting the normal segment of DNA and inserting the gene drive (Figure 1, bottom). As such, all progeny of a gene drive mosquito will carry not 1, but 2 copies of the gene drive, allowing the gene drive and its associated malarial resistance gene to spread through the mosquito population at an unprecedented rate. Ideally, this would slow or even stop the spread of malaria over time.

What is the potential of gene drives for preventing diseases?

Gene drives have broad applications for preventing the spread of diseases transmitted by insects, with malaria being just one example. Many other vector-borne diseases such as dengue, Lyme, and Zika can be curbed in a similar manner. Gene drives also have applications for controlling drug resistance mechanisms. Early studies have demonstrated that gene drive technology can be used to target fungi that spread disease and limit their ability to mutate to become drug-resistant.

Additionally, gene drives have broad implications for agriculture. For example, it can be used to increase total crop yield by altering weeds (such as ragweeds that choke out soybean crops, as aforementioned) or reducing the presence of organisms that cause crop damage. Gene drives could also be used to reduce populations of other invasive species, such as rodents.

Gene drive outlook                                            

There are concerns that need to be taken into consideration before gene drives are applied broadly to organisms. For example, scientists worry about the potential other unintended (off-target) effects of CRISPR/Cas9 technology, such as indirect impact on other genes in the organism that could result in death or inability to reproduce. Moreover, the time required for the effects of gene drives to spread through the population needs to be further studied. Finally, by altering one organism, there could be potential issues with disrupting the balances of other organisms that are dependent on the altered species, such as the predators of the organisms. These problems must be carefully studied and understood prior to introducing gene drives into the ecosystem.

Once scientists have carefully addressed these challenges, gene drives have great potential for disease preservation and the reduction of invasive species. Scientists have already demonstrated the efficacy of using gene drives in organisms such as fruit flies and mosquitos, and groups around the world are working to develop the use of CRISPR/Cas9 in gene drive systems. It will be an exciting ride to see the changes gene drives bring in the future!

Jessalyn Ubellacker is a recent PhD graduate from the Biological and Biomedical Sciences Program at Harvard Medical School 

For More Information:

• For more information about gene drives, check out this article from Harvard’s Wyss Institute
• To learn more about gene drives against malaria, see this PNAS paper

 

This article is part of the 2018 Special Edition — Tomorrow’s Technology: Silicon Valley and Beyond