Signs of Spring 13: Gene Drives

Photo by D.G.E.Robertson, Wikimedia Commons

Earlier this year I read an article in The New Yorker (January 2, 2017) in which a program designed to change the genome of the white-footed mouse was discussed. This change would make these mice (which are the principle biotic reservoir for Borrelia burgdorferi (the bacterium that causes Lyme disease)) unsuitable hosts for that bacterium. If this could be accomplished, the passage of B. burgdorferi from white-footed mice to and from black-legged ticks (Ixodes scapularis) could be stopped and the ticks’ transmission of this bacterium to hundreds of different vertebrate hosts (including humans) would be severely disrupted. This could result in the ecological control of Lyme disease.

For the last several years, Pennsylvania has led the nation in the number of human cases of Lyme disease (in 2014 there were 7487 conformed human Lyme disease cases in Pennsylvania up from 5904 cases in 2013). Further, the Center for Disease Control (CDC) states that the number of reported Lyme cases in the United States (30,000 in 2014) represents only 10% of the actual number of infections.

Borrelia bacteria, CDC, Public Domain

Dogs can also develop Lyme disease. Most dogs (95%) that receive the Borrelia bacterium via a tick bite show no symptoms at all. The dogs that do react to the bacterial infection often develop lameness in one of their legs that typically lasts for a few days. The lameness can then shift to another leg and can be quite debilitating. In some dogs the Lyme infection can also lead to kidney disease and even kidney failure. The actual number of dogs infected each year by B. burgdorferi is not known. Informal reporting from local veterinarians, though, indicates that the number is large (and increasing each year!).

Any plan that focuses on an ecological solution to this epidemic disease should be given serious consideration. The control project described in The New Yorker article has two very straightforward and technologically elegant phases that are based on some very significant, cutting-edge molecular biological developments.

CRISPR, J. Atmos, Wikimedia Commons

In the first phase of the project, CRISPR is used to insert a gene directly into the white-footed mouse’s DNA. CRISPR is a technology that employs specifically engineered RNA sequences and a protein that cuts (and pastes) DNA in order to line up a sequence of DNA at a specific gene locus and then insert it into the DNA strand.

The second phase of the project utilizes a recognized interaction between an organism’s homologous chromosomes (the two coding strands of DNA (plus proteins) that carry the organism’s two different versions of all of its genes). In this interaction one of the homologous chromosomes contains a specific DNA sequence that makes an enzyme that spontaneously cuts the DNA sequence of the other chromosome. This is very similar to CRISPR except that in this system the “cutting” gene sticks a copy of itself into the severed DNA sequence. This second system is called a “gene drive,” and it results in the amplification of a gene passing through generations in a population.

CRISPR was first observed in bacteria and is used by these types of cells to store and pass along to subsequent generations the immunological memories of virus exposures. The Broad Institute of M.I.T has an excellent “question and answer” web posting about CRISPR if you would like to read more about it.

Gene drives occur in many natural genetic systems and are mechanism by which genes, even if they are not beneficial to the species, can rapidly build up in a population. . If you would like to read more about gene drives please see the “FAQ’s about gene drives” posed by the Wyss Institute of Harvard.

The essential idea of this Lyme disease control project is to make a DNA sequence that codes for an anti-Lyme antibody protein and then insert it into the white-footed mouse’s DNA along with a gene drive! These genetically altered mice would be “immune” to the Lyme bacterium and, when released into a wild population, they will spread the gene-driven antibody gene very rapidly through the entire white-footed mouse population. Eventually, these white-footed mice would be free of  Borrelia burgdorferi and Lyme disease would no longer be transmitted or amplified by them!

The scientists of the Lyme control program are looking for a small island on which the controlled release of the altered mice could be closely monitored. A number of island communities here in the East (where Lyme disease has become an exponentially expanding problem in human (and dog) populations) have already volunteered to be the anti-Lyme test site. Unease and uncertainty about the unintended consequences that might arise from the release of genetically altered organisms into our ecosystems, though, represent significant ethical and ecological concerns that need to be thoroughly evaluated before this experiment is carried out.

Other pathogens dispersed by targetable vectors are also being considered for similar types of genetic modifications and gene drive insertions. Control systems for malaria, for example, were discussed in an article by Tony Nolan and Andrea Cristanti in  The Scientist earlier this year (January 1, 2017).

Anopheles mosquito, CDC, Public Domain

For years, Nolan and Crisanti report, scientists have been working to sequence the complete genome of the various Anopheles mosquito species that are responsible for most of the transmission of the protozoan parasites (Plasmodium spp.) that cause malaria. With the complete Anopheles genome now in hand, researchers can begin to identify the specific genes that allow Plasmodium to live and reproduce inside of the Anopheles mosquito. They are also

Mature Plasmodium in blood, CDC, Public Domain

looking for those genes needed to transmit the Plasmodium life stages to bite victims through the mosquito’s saliva. Once these genes are identified, altered versions that act to block the Plasmosium life cycle or prevent transmission could be engineered and inserted (with gene drives) into the mosquito’s DNA.  Release of these gene-driven mosquitoes into a wild population of malaria carrying mosquitoes, then, could disrupt the transmission of Plamodium and, possibly control the disease.

Other ideas for mosquito control (and, thus, malaria (or Zika or Denge or encephalitis or West Nile virus) control) involve inserting genes (with gene drives) that disrupt mosquito reproduction or sex ratios. These genetic modifications could result not just in disease control but possibly the extinction of an entire mosquito species! When you consider the “good” things that mosquitoes do in an ecosystem (Signs of Spring 13, May 19, 2016) this plan for extinction is very disturbing.

We are the verge of having some very powerful new tools to fight disease. We must be careful, though, to see beyond our short-term goals of disease control and be sure that we understand the long-term ecological and even evolutionary impacts that the use of these tools may trigger! Ecosystems much more complex than they appear, and some changes can have completely unanticipated consequences!

 

 

 

 

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One Response to Signs of Spring 13: Gene Drives

  1. Jennifer Wood says:

    Another great post, Dr. H! I read that New Yorker story, too, and am grateful for your take on it. I’d love to see Lyme disease (and Zika and malaria and Denge and and and!) eradicated but not without knowing the long-term consequences.

    Our vet recommended a Lyme vaccine for our dogs. I asked her if there’s one for me, too! 🙂 It’s interesting that there’s a vaccine for dogs but not one for humans. I wonder what made a dog vaccine possible and what are the obstacles for developing one for humans.

    Love this blog. Thanks for keeping it up!

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