Understanding Synthetic Biology and Gene Drives

Synthetic biology combines techniques from molecular science and genetic engineering to change the natural genetic makeup of living organisms to favor certain traits. While molecular cloning is an early and familiar technique, synthetic biology has been drastically improved in recent years with gene drive technology, especially CRISPR/Cas9. Designed to spread a chosen trait throughout a wild population to reduce its size, this technique can control invasive species or pests such as disease-carrying mosquitoes.

Synthetic biology is the scientific field of artificially redesigning existing biological systems, modules and living organisms (Nakano et al., 2013; Osbourne et al., 2012). It is a combination of various technologies such as molecular science, genetic engineering and computer engineering to change the natural genetic makeup of living organisms to favor certain physical and ecological traits that are primarily for the benefit of human beings, and not necessarily that of the modified organisms (Osbourne et al., 2012). Modification of living organisms is achieved by manipulating their genetic makeup and inserting specific genes of interest that these organisms pass on to their offspring through sexual breeding. These specific genes of interest may be responsible for many physiological characteristics, including pest resistance in plants and tropical heat adaptation by animals.

 

Synthetic biology is a rapidly expanding field wherein engineering principles are applied to the construction of biological parts and systems, resulting in new and desired traits that are lacking in their original or natural state (Carlson, 2010; Church & Regis, 2014).

 

Molecular cloning is one of the early scientific technologies widely used to modify the genetic makeup of living organisms and probably the most widely used in synthetic biology. In molecular cloning, DNA fragments or recombinant DNA are inserted into a host organism (Figure 1) for it to express the desired gene traits such as the synthesis of proteins like insulin or efficient production of bio-fuel, medicinal compounds and others. In fact, DNA cloning is becoming obsolete and science has moved on to other highly efficient techniques. Such technologies have sped up the rate by which humans modify living organisms and consequently the biological systems in which these modified organisms live.

 

The modification of biological systems and the environment in which we live is an old and common practice in the history of human colonization. Humans continuously contribute to the alteration of their environment and, ultimately, the ecosystem, on which they have been dependent since time immemorial. For example, the shift in sustenance practices from hunters and gatherers to subsistence farming and commercial farming is the direct result of the introduction of technologies and machineries.

 

Farming techniques, the selection of high-yielding plant breeds, and cross-breeding of animals to produce better progeny were an established part of human prehistory. From the ancient technology of simple plant and animal selection, still the primary technique into the 1700s, to cross-breeding of plants in the 1800s, to the cloning of Dolly the sheep in the 2000s (Figure 2), the history of human interaction with the environment utilizing various techniques clearly demonstrates humanity’s effect on the food ecosystem.

 

Synthetic biology is a combination of various technologies such as molecular science, genetic engineering and computer engineering to change the natural genetic makeup of living organisms to favor certain physical and ecological traits that are either beneficial to these organisms or human beings. It is best understood as the rational design of biological systems and living organisms using engineering principles (Osbourne et al., 2012). It is not simply a platform, but a bold and new way of thinking that helps us to understand biological processes and systems.

 

Advances in synthetic biology include the construction of a synthetic biological pathway to manufacture artemisinic acid, a precursor for the anti-malarial drug artemisinin in microbes (Ro et al., 2006; Westfall et al., 2012) or the synthesis of a novel functional microbial genome de novo (Gibson et al., 2010). It is clear that these modifications are pursued primarily to humanity’s advantage.

 

Synthetic biology has been drastically improved in recent years for higher precision and efficiency due to gene drive technology, especially Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) and particularly, CRISPR-associated system 9 (Cas9) or CRISPR/Cas9.

 

Mature CRISPR RNA (crRNA) guides Cas9 to the target site of invading phage DNA. The DNA single-strand matching crRNA and opposite strand are cut, respectively, by the HNH nuclease domain and RuvC-like nuclease domain of Cas9, generating a double-strand break (DSB) at the target site. The specificity of CRISPR/Cas9-mediated DNA cleavage requires target sequence matching crRNA and a 3-nt PAM located downstream of the target sequence (adopted from Zhang F et al., (2014)).

 

CRISPR/Cas9 is a gene drive technology designed to spread a chosen trait (e.g., producing infertile offspring throughout the wild population to reduce the population of invasive species  or pests), which may ultimately lead to total extermination or eradication. Gene drive functions by distorting inheritance via increasing the natural 50:50 chance of inheritance to more than 50% in favor of the genetically modified species. Over successive generations, that gene will become dominant in the wild population. This has been greatly harnessed by the use of the CRISPR-Cas9 gene-editing tool technology that allows scientists to modify an organism’s genome precisely (Esvelt & Gemmell, 2017).

 

It is a very a powerful tool with the ability to intervene in evolution and modify ecosystems. It also has the potential to be a dangerous technology because it lacks evaluation on its ethical and social impacts, may unleash unwanted large-scale environmental changes, may hypothetically be used by the military as a biological weapon, and has unregulated widespread use in agriculture (e.g., genetically modified organisms (GMO)).

 

In the Pacific, there are a few examples of gene drives that are currently in use or consideration, including extermination of invader rats, stoats and possums in New Zealand. Gene drive distorts normal (“wild”) patterns of inheritance. Gene drive systems distort the natural inheritance system. With the use of CRISPR-based gene drive systems to distort the genetic makeup of rats, resulting in a reduction in the production of fertile offspring. Consequently this leads to an extermination of the rat population over time.

 

Eradication of Aedes polynesiensis mosquitoes in selected Pacific Islands

 

There are numerous cases of gene drives being used to eradicate mosquitoes in the Pacific. Aedes polynesiensis mosquitoes in Tahiti were infected with the Wolbachia bacterium and released into the wild to mate with other mosquitoes. Resulting eggs develop incorrectly and will not hatch, thereby reducing its population. The Wolbachia bacterium was also introduced to dengue transmitting mosquitoes (Aedes aegypti) in Fiji and Vanuatu. If successful, the gene drive will make A. aegypti sterile and prevent the spread of the dengue virus. In Hawai’i, researchers implemented a gene drive to control avian malaria by releasing insects carrying a dominant lethal (RIDL) technique, targeting the reduction of Aedes aegypti mosquitoes.

 

Other potential gene drive targets in the Pacific which will certainly have an impact on biodiversity conservation are the eradication of invasive rodents, taro leaf blight diseases (Samoa, Fiji), coconut beetles in the Solomon Islands, giant African snails (Samoa, Solomon Islands) and black ants infesting homes in Fiji.

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