Contemporary problem essay

Australian Strategic Policy Institute

Report Part Title: GENETIC MODIFICATION

Report Title: Biodata and biotechnology Report Subtitle: Opportunity and challenges for Australia Report Author(s): John S Mattick Published by: Australian Strategic Policy Institute (2020) Stable URL: https://www.jstor.org/stable/resrep26124.6

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GENETIC MODIFICATION

Genomic information is the raw material for genetic engineering.

Genetic engineering, as opposed to the genetic selection practised since time immemorial in the agricultural, animal breeding and fermentation industries, has its roots in the manipulation of genes in microbial hosts during the 1970s to produce pharmaceutical products such as human insulin. The technical complexity of genetic engineering in plants and especially animals is much greater and has largely been limited to introducing gene sequences that confer viral or insect resistance or disable particular genes, such as those involved in ripening, to extend the shelf lives of products.

The ease and precision of genetic engineering have been transformed with a discovery that came out of left field (in another example of the beautiful serendipity of research and how rapidly the landscape can change), in this case of a viral defence system in bacteria that’s been adapted to allow DNA changes, insertions or deletions in the genome of any organism.

This system is called CRISPR, an acronym derived from the characteristics that were first noticed in strange repeated sequences in bacterial genomes.* The technological innovations that have ensued have been extraordinary,144,145 the latest enabling relatively error-free insertion by RNA guide molecules of any desired sequence at any specific position in the genome (termed ‘prime editing’).146 CRISPR is now being widely used to alter genomic information in research, human medicine, pastoral animals, agriculture and industrial biotechnology.144,145,147

Human gene therapy and repair CRISPR prime editing has been shown to correct the genetic causes of the inherited genetic disorders Tay–Sachs disease and sickle cell anaemia and has the potential to correct the majority of known genetic variants associated with human diseases.146 There are also other systems, less efficient but nonetheless effective, for gene editing using engineered sequence-specific DNA binding proteins.

Such genetic repairs are mainly confined to those that are feasible to undertake after birth by, for example, the reintroduction of engineered blood cells or injection into affected tissues, such as the eye. In many if not most genetic disorders, the damage is already done, although some are amenable to lifesaving treatments, including dietary modification or supplementation. It’s possible that in future damaged genes may be repaired in embryos but, in practical terms, many if not most debilitating monogenic disorders will be simply avoided, once genomic sequencing is routine, by preconception screening and subsequent embryo selection in at-risk couples to avoid those that are compromised,† as commonly occurs at present with chromosomal disorders such as Down syndrome.

* CRISPR = clustered regularly interspaced short palindromic repeats. † Such selection is independent of other characteristics and, at least for recessive genes, doesn’t appreciably change the allele

frequency in the population, which allays concerns about longer term unintended consequences. Genetic disorders in the heterozygous state confer resistance to diseases, such as cystic fibrosis (resistance to cholera) or sickle cell anaemia and thalassaemia (resistance to malaria).

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20 BIOdATA ANd BIOTECHNOLOgy: OPPORTUNITY AND CHALLENGES FOR AUSTRALIA

Genetic engineering of virulence or replication genes in human viruses has been undertaken for many years to make them suitable as gene therapy delivery vehicles148 or attenuated vaccines.149

Ex vivo genetic engineering of patients’ immune cells, notably synthetic ‘chimeric antigen receptor’, or CAR T-cell therapy, is being used successfully to target antigens present on haematopoietic (blood) cancer cells and shows promise for solid tumours.150 CRISPR has also been successfully used to eliminate the HIV retrovirus from the genome in mice,151 and there have been promising results in a human patient.152

There has been one case of so-called germline editing, carried out in China, to alter a gene in embryos to confer resistance to HIV-AIDS.153 This has been widely condemned and prompted international efforts to restrict human reproductive engineering.

Our ability to make sensible changes to the human genome, or the genome of any complex organism, is limited by our currently poor knowledge of genomic information, especially the genetic factors associated with complex traits such as athletic or musical ability, personality154 and logical or creative intelligence, among the many dimensions of human biology and diversity. In most cases, we don’t know the identity of the specific genetic variations involved and, in any case, most have minor effects and operate in networks, in which a benefit in one dimension may be a handicap in another. While there’s no doubt that humans will ultimately have sufficient knowledge to guide their own evolution, that day is a long way off, even if it does engender much debate in the interim.

Genetic engineering of microbes, plants and animals Things are of course simpler in other organisms, but genetic engineering is still largely limited to simple subtractions or additions of genes or suites of genes.

Gene subtraction includes the deletion of the ‘poll’ gene for horns in cattle,155 the disabling of the myostatin gene, which negatively regulates muscle growth to increase muscle mass (meat yield) in merino sheep, goats and pigs,156 and the deletion of specific genes in pigs to obtain resistance to viral gastroenteritis157 and porcine respiratory and reproductive syndrome.158,159

The addition of new capabilities is the ambition of the nascent field of ‘synthetic biology’, or ‘genome printing’, and is based on the demonstration that complete viral and even bacterial genomes can be assembled in the test tube and inserted into a blank viral capsid or cell to create a viable organism. This means, in theory, that any new type of bacteria or virus, with new genetic circuits, can be designed in silico and made viable in any reasonably well-equipped laboratory. The construction of synthetic animal and plant genomes from scratch is not yet possible, and may never be possible, although it may be possible to reverse-engineer existing species to recreate extinct ones or make new ones.

Designer changes can and are being made across the board, with increasing range and sophistication. The addition of new genetic capabilities has led to the development of new strains of animals, plants, yeasts and bacteria with better growth rates, new metabolic capabilities and enhanced disease resistance, among many other characteristics.160

Examples include the introduction of the biosynthetic pathway for beta-carotene synthesis in ‘biofortified’ or ‘golden’ rice, bananas* and potatoes161-163 to increase vitamin A content (lack of which causes blindness in an estimated 250,000–500,000 children annually), and ‘purple’ rice, which has been engineered to produce the antioxidant compounds found in blueberries,164 although take-up has been dogged by largely irrational campaigns against genetically modified plants. The introduction of the bacterial insect ‘Bt’ toxin† into cotton, corn and other crop plants has, in fact, led to massive reductions in insecticide use, with far less collateral damage to other insects in the ecosystem, and with no evidence of harm to human health or the environment.165 Some 99.5% of cotton

* Developed at the Queensland University of Technology. † More than 200 Bt toxins are naturally produced by the soil bacterium Bacillus thuringiensis, cultures of which are sprayed on

plants in ‘organic’ farming.

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21GENETIC MODIFICATION

planted in Australia) is genetically engineered.166 Almost paradoxically, such crops are more ‘organic’ than they were previously.

Plants have also been engineered for resistance to a wide range of viruses167 and to control ripening (to extend shelf life), flowering time and plant architecture in many fruit and horticultural species, including tomatoes, strawberries, apples, kiwifruit, grapefruit, watermelons and cucumbers.168 As with human genome sequencing, China is investing heavily in genome editing for crop improvement.169

In animals, examples include the introduction into cattle of a gene that confers resistance to tuberculosis170 and the introduction of a growth hormone gene (from Chinook salmon) into Atlantic salmon, which enables the salmon to grow faster and to reach the same size with 25% less food.171 Trials are underway to insert or modify sex determination genes to bias sex ratios in the beef and dairy sectors,172 as well as in poultry, silkworms and pest control.173

Such designed modifications increase the efficiency and quality of food production, as well as reducing waste and environmental damage. The future will also bring a universe of bio-innovations, including bacteria engineered to produce, for example, spider silk,174 which is stronger per unit weight than high-tensile steel,175 as well as other biomaterials for industrial and medical applications, such as tissue regeneration.176

National and social security The immediate concern for national security is the use of genetic engineering for bioterrorism or state-sponsored harm.

Bacteria can be easily engineered, even in a backyard laboratory, to carry lethal toxins, but they’re difficult to disseminate and relatively easy to contain.

Not so with viruses. The topic du jour is the concern that the virus that causes Covid-19 may have originated in, or at least escaped from, a laboratory. That might or might not be the case, but it was almost certainly not designed there, if for no other reason than that we don’t yet know enough about the idiosyncrasies of the proteins in viruses that allow them to infect human cells. Therefore, it’s essentially impossible at present to design specific genetic changes to that end, even if the technology for engineering viral gene sequences is straightforward.

On the other hand, it may be easy to isolate virus variants that can infect humans by selection for growth in cultured human cells, although this often causes the attenuation of virulence.177 It’s possible to make existing viruses more lethal by engineering in genes that attenuate immunological responses, although such viruses may also be less contagious.178

In any event, it’s almost impossible to prevent the spread of new natural, selected or purposely engineered viruses that have high infectivity, except by national quarantine, which comes at considerable economic and social cost, and the development of vaccines or treatments, which takes time. As Covid-19 demonstrates, such viruses may be by far the biggest threat to national security, as broadly defined, and an easy weapon for adversaries that have different values from ours. The protection against this is the development of rapid-response capability, including the fast-tracking of vaccines and antiviral drugs.

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