Eradication of entirespecies – What has become possible with Gene Drive and CRISPR

The genetic modification of not only the characteristics of individuals, but the permanent genetic manipulation of entire populations is one of the biggest dreams – or, depending on the reading nightmares – of geneticists. The effects would be enormous: For example, insects such as tsetse flies or mosquitoes could be modified throughout their entire species to be immune to parasites that cause disease in humans and thus be unable to transmit them.

The genes of individual living organisms can easily be manipulated by various meanstoday. In contrast a fundamental barrier has long prevented scientists to enforce specific genes in an entire population. According to classical genetics, for (sexually reproducing) living beings sometimes the characteristic of the mother, sometimes the ones of the father, and sometimes even the ones of a grandparent are passed on to the next generation So it is a matter of chance whether a desired mutation – random or intentional – transfers to the next generation or not. So to curb sleeping sickness in humans, it is not enough to release a few genetically modified tsetse flies that are immune to the pathogens near settlements. It would take a very, very large number of insects to make an entire (wild) population less dangerous. This is usually impossible in practice.

For 15 years, however, scientists have known a kind of turbo for the inheritance of altered gene, so that they are more likely to be passed on as usual to the offspring. The biologists speak of “gene drive”. Gene drive also occurs in nature when certain genes use molecular mechanisms to help their chances and achieve higher transmission rates. However, this happens uncontrollably and at indeterminate times. In 2003 biochemist Austin Burt came up with the idea of artificially producing this hereditary turbo. The goal is to bring the natural value of hereditary transmission of altered genes from approximately 50 percent closer to 100 percent.

However, until about five years ago, the applications of the gene drive were very limited, since the genetic templates for splitting the DNA at the desired site (the so-called endonucleases) must correspond to the desired sequence on the DNA. Bioengineers did not have this flexibility with the available endonucleases. With the discovery of the gene editing process CRISPR in 2012, this changed abruptly. “CRISPR” stands for “clustered regular interspaced short palindromic repeats” and describes certain sections of repeating DNA fragments in the genome of bacteria. To these DNA pieces, the endonuclease “Cas9” is added (there are also other similar mechanisms with other enzymes). The composite of these two is of particular interest to genetic engineers as it acts like Lego bricks finder and scissors at the same time. Genetic engineers populate the CRISPR / Cas9 enzyme complex with a sequence that is exactly complementary to the desired target DNA sequence. This total complex then finds the desired target sequence in the DNA and cuts it exactly there. Thus, a suitable endonuclease is found for each site on the DNA, such that at any desired location a new gene sequence can be installed or an old be removed without replacement.

CRISPR opens a path to installing a gene drive mechanism so that with only a few dozen or a few hundred manipulated and then released individuals, a desired genetic change can be introduced into an entire population. For this purpose, not only are certain gene segments in the sperm or egg DNA selectively modified, but also is the appropriate CRISPR / Cas9 complex integrated into the genome. Once fertilization has taken place and the two haploid homologous chromosome strands (the manipulated and the “wild”) are joined together, CRISPR / Cas9 cuts the corresponding unwanted gene from the wild-type chromosome. Left intact is the genetically modified strand, which now serves as a template for the fragmented DNA strand: To fill the gap, the repair mechanism of the cell simply copies the engineered gene along with the CRISPR / Cas9 complex into the dissected chromosome. Thus, eventually both chromosome strands carry the genetic change. As with a snowball system, it is then duplicated with each new generation and passed on to all descendants. Each time another gene variant is added at fertilization, it is removed and replaced with the copy of the altered gene. So CISPR / Cas9 provides biotechnologists with the long desired tools to quickly and permanently change entire populations with gene drives.

The possible applications are indescribably exciting. For every problem, it would be possible to construct a tailor-made gene drive solution that would make pathogens harmless or permanently give certain properties to plants. Scientists are already talking about “sculpting evolution”. Ineradicating diseases transmitted by insects, such as malaria or the dengue or Zika virus, this technique would be very helpful and surely be welcomed by many.

And indeed, just a few days ago scientists from the Empirical College in London published a gene drive that allowed a whole population of mosquitoes to die off in just a few generations (A. Crisanti et al., A CrisPr-Cas9 gene drive targeting doublesex causes complete population suppression in caged Anopheles gambiae mosquitoes, Nature Biotechnolgy, 24 Sept 2018). The gene introduced by the team led by Andrea Crisanti aimed at sex determination. In essence, they prevented female offspring from being produced. The population experimented with was still in a closed space. But once released into the wild, the new method could eradicate malaria by simply eliminating its transmitter, the mosquito Anopheles. Every year, one million people die from this disease. Accordingly, tropical medical doctor and biologists are pleased about this success.

However, because of its enormous potency, the new CRISPR gene drive method is also highly problematic: how do we control the altered genes? Do they continue to mutate? Furthermore, It has been proven that different species can exchange genes. What happens when a gene is transmitted in a different way and suddenly produces completely new, undesirable properties? What does it mean for us when entire ecosystems change abruptly? A technology that can systematically eradicate entire species raises ethical issues the impact of which scientists and policymakers are only beginning to understand. One the one hand the lives of millions of people saved from starvation and diseases like malaria, on the other hand the existence of a few unwanted plant and animal species and the risk of an unexpected ecological revolution – how can we find the right balance between these points? And what sounds exciting when applied to disease transmitting insects soon becomes eerie, if applied to higher-developed organisms or even to humans.