Written by Lorenzo Mahoney ‘24
Edited by David Han ‘24
Our grandparents grew up in a world that didn’t understand how a gene becomes a protein. Nowadays, whole genomes can be characterized within hours and each gene’s function is predicted with relative ease. The field of molecular biology has progressed from discovering building blocks to becoming the builders, creating engineered organisms and genetic recombinants. Much like advancing from the Stone to the Iron Age, basic tools have given way to manipulating natural systems for increased productivity. The major difference between these two trajectories of innovation is their time horizons. History’s advancement took hundreds of thousands of years, whereas molecular biology has risen in under a century. With such an intense rate of acceleration, upcoming decades are bound to include exciting and life-changing discoveries. But the Iron Age didn’t just produce stronger tools for grain collection, but also more powerful weapons. Greater power over biological systems and the commercialization of human-programmed organisms are likewise unlocking nefarious futures. In response, research in molecular biology must balance progress with precaution.
The current landscape of biological engineering has worked on optimizing biological networks to create ‘genetic circuits’ with real-world applications. By introducing genes into model genomes and adding co-factors to upregulate their production, scientists have been able to generate microbial ‘cell factories’ programmed to mass-generate valuable chemicals for pharmaceutical use. For example, the drug artemisinin is a powerful anti-malarial drug but expensive to artificially produce or collect from plants. With bioengineering, transducing specific genes into yeast cells makes creating costly intermediates much more accessible [1]. Key enzymes from wormwood, a traditional medicinal plant to treat malaria, extend yeast’s cholesterol-forming pathway and generate substantial amounts of the highly sought artemisinic acid, an immediate precursor to the target anti-malarial. By 2016, 39 million artemisinin treatments used a semi-synthetic approach [2]. In cell factories like these, genes are expressed constantly and their products are maximized. In other situations, more nuance is needed. Genetic circuits can be conditionally activated through external stimuli. The infectious pseudotuberculosis gene invasin confers bacterial invasion into mammalian cells. Invasin functions at the cell’s surface, interacting with animal cell receptors and triggering the host to consume the parasite through phagocytosis. Under cell factory conditions, E. coli making massive amounts of invasin would lead to mass infection. However, placing invasin under the control of cellular sensors derived from fluorescent microbes activates its production only when nearby cell density is high. By combining cell features from a range of bacteria, you have a recipe to direct programmed cells to invade cancerous cells as a vehicle for tumor suppression [3]. Such tinkering and cross-species combination can deliver positive outcomes in drug production and medical treatment, but their mosaic status and irregular capabilities can also generate organisms with the ability to hurt more than heal.
Within manipulated cells, novel drug pathways could generate carcinogenic byproducts or allergens. At an environmental level, synthetic organisms can outcompete native versions, leading to compromised biodiversity and ecological balance [4]. In the wild, there is also the possibility for horizontal gene transfer, where genetic information is exchanged between different organisms, specifically bacteria [5]. If a synthetically designed superbug came into contact with a benign organism, it could transfer antibiotic resistance genes to unintended species. Even more complicated is the possible transfer between two genetically modified genomes of already specialized genes, which can develop a ‘stacking’ of target gene interactions, going far beyond what researchers were aware of.
The dangers of synthetic biology don’t just lie within the organisms that are created, but also in the people creating them. With the rise of the field and genetic engineering technology becoming more accessible, many have pointed out the corollary threat of bioterrorism. Genomes of deadly viruses are publicly available and deliverable. Unbelievably, Canadian researchers were able to construct an extinct horsepox virus by combining mail-order genome fragments without any regulation barriers (despite it being illegal) [6]. The potentials of synthetic organisms have shown great promise, but their manmade alterations bear less resemblance to native species and carry more destabilizing power, whether intentional or not.
Knowing the risks associated with creating extreme forms of life, the laboratory has turned inward from innovation to containment. Synthetic organisms are normally designed with very stringent survival conditions. Targeted genes are often conditionally activated by specific and unnatural chemicals only present in lab settings. Still, controlling viability through a single, niche interaction could be derailed by a random mutation. Layering safeguards atop one another provides greater insurance. In the previously mentioned cancer-targeting E. coli, the biological sensor was controlled simultaneously through oxygen-lacking and sugar-specific promoters [3]. Promoters are DNA sites with specific molecular binders that initiate downstream gene expression. E. coli can’t invade cells if its sensor isn’t present when there is either oxygen or the sugar supplement arabinose aren’t present. Besides creating more complex and cascading systems, another protective measure is creating organisms so unnatural that nature can’t be hurt by any genetic spillover. A collection of researchers have proved it possible to alter the chemical language of key enzymes by incorporating manmade nucleotides and amino acids [7]. As this laboratory-only practice becomes more widespread, engineered cells become dependent on non-canonical building blocks and the threat of horizontal gene transfer and unintended proliferation is minimized.
The far-reaching consequences of genetically engineered organisms, like bettering pharmaceutical production and worsening the threat of bioterrorism, have drawn the attention of scientists and policymakers alike. The ‘dual-use dilemma’ of biological research deserves governance and regulation within and beyond borders (8). But between the worlds of science and government, there is some disconnect between achievement and understanding. The rapid pace of biological discovery has forced state agencies to deliver quick judgments on new areas of interest. In the United States during the 2000s, the National Research Council declared that synthetic biology is not any different or more dangerous than previous genetic engineering ventures [9]. Fast forward a decade, government agencies were stressing biocontainment as imperative for recombinant organisms [10]. As the number of commercially designed microbes increases, some fear their complexity and abundance may be too much for centralized EPA authorities to handle [10]. As we further understand the science of life and unlock new masteries over cellular processes, we could be heading into biology’s renaissance or its dark ages.
References
1. Ro DK, Paradise EM, Ouellet M, Fisher KJ, Newman KL, Ndungu JM, et al. Production of the antimalarial drug precursor artemisinic acid in engineered yeast. Nature. 2006 Apr;440(7086):940–3.
2. Peplow M. Synthetic Biology’s First Malaria Drug Meets Market Resistance [Internet]. Scientific American. 2016 [cited 2022 Nov 19]. Available from: https://www.scientificamerican.com/article/synthetic-biology-s-first-malaria-drug-meets-market-resistance/
3. Anderson JC, Clarke EJ, Arkin AP, Voigt CA. Environmentally Controlled Invasion of Cancer Cells by Engineered Bacteria. Journal of Molecular Biology. 2006 Jan 27;355(4):619–27.
4. Hewett JP, Wolfe AK, Bergmann RA, Stelling SC, Davis KL. Human Health and Environmental Risks Posed by Synthetic Biology R&D for Energy Applications: A Literature Analysis. Applied Biosafety. 2016 Dec;21(4):177–84.
5. Nielsen KM, Johnsen PJ, Bensasson D, Daffonchio D. Release and persistence of extracellular DNA in the environment. Environmental Biosafety Research. 2007 Jan;6(1–2):37–53.
6. Noyce RS, Lederman S, Evans DH. Construction of an infectious horsepox virus vaccine from chemically synthesized DNA fragments. PLoS One. 2018;13(1):e0188453.
7. Mandell DJ, Lajoie MJ, Mee MT, Takeuchi R, Kuznetsov G, Norville JE, et al. Biocontainment of genetically modified organisms by synthetic protein design. Nature. 2015 Feb;518(7537):55–60.
8. Wang F, Zhang W. Synthetic biology: Recent progress, biosafety and biosecurity concerns, and possible solutions. Journal of Biosafety and Biosecurity. 2019 Mar 1;1(1):22–30.
9. National Research Council. Safety of genetically engineered foods: Approaches to assessing unintended health effects. 2004;
10. National Institutes of Health (U.S.). NIH guidelines for research involving recombinant or synthetic nucleic acid molecules. Department of Health and Human Services; 2019.
11. Carter SR, Rodemeyer M, Garfinkel MS, Friedman RM. Synthetic Biology and the U.S. Biotechnology Regulatory System: Challenges and Options [Internet]. J. Craig Venter Institute, Rockville, MD (United States); 2014 May [cited 2022 Nov 11]. Report No.: DOE-JCVI-SC0004872. Available from: https://www.osti.gov/biblio/1169537
[Image] Labster Theory. Synthetic_biology.jpg [Internet] [cited 2022 Nov 19]. Available from: https://s3.amazonaws.com/labsterim/media/uploads/Synthetic%20Biology/synthetic_biology.jpg
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