Synthetic Biology: An Era of Promised Uncertainty

Forget meeting our Maker, the question now being asked is: have we become our Maker? Or is John Craig Venter simply exaggerating the importance of his team's latest achievement? Algae releasing oxygen bubbles as a by-product of photosynthesis, the process of using sunlight to convert carbon dioxide and water into oxygen and biomass. It is this biomass that has the potential to be converted into a range of biofuels (Costa and De Morais, 2010).

Source: Conrad, J., 2008. Algae oxygen bubbles. [electronic print] 
Available at: http://www.backyardnature.net/n/08/080721ag.jpg [accessed 22 August 2010]

The J. Craig Venter Institute announced in May that they had successfully created the "first self-replicating synthetic bacterial cell" after a fifteen year quest (1). However, the extent to which this bacterium is "synthetic" has been subjected to intense debate. "Venter's team is relying on the information in a natural genome," says Peter Dearden, Director of Genetics Otago, who argues that Venter's team has not created life, but has made a significant step toward it. "While the DNA strand that makes up the genome is synthetic and made in the lab, the information it contains comes from a species of bacterium; and it is the information that is important in a genome. Venter's team needs a bacterial cell, one without a genome, to put their synthetic genome into," Dearden argues. "This cell, currently, can only be made by a living organism" (2).

Irrespective of whether the species is 100% man-made, it's still a remarkable feat. Before this triumph, geneticists literally "cut and paste" (3) genes from one organism to another. This approach meant that researchers had very limited control over modifying the bacterium as they worked on a gene-by-gene basis.

Venter, on the other hand, synthesized an entire genome – more than 1 million base pairs – all at once. This accomplishment is paving the way for researchers to "code" new genomes using a computer model that can digitally write out, base by base, any sequence (4). Geneticists might one day use this technology to manufacture countless novel species at the push of a button.

Venter used the decoded genome of the small bacterium Mycoplasma mycoides to build the artificial genome. First, Venter and his team created short DNA segments and inserted them into yeast cells. The yeast cells resembled a microscopic factory, assembling the DNA fragments into a final genome. The result – officially named M. Mycoides JCVI-syn1.0 – is a fully-functioning, self-replicating, bacterial Frankenstein, which Venter nicknamed "Synthia" (5).

In order to differentiate between the wild type (or naturally-occurring) and the synthetic genome, Venter's team inserted four stretches of DNA into the synthetic DNA species. These sequences, consequently, are unique to Venter's synthetic genome and can be used to trace the organism back to the laboratory in which it was created. These "watermarks" use a secret code based on the four bases in DNA – A, C, G and T – in order to spell any letter in the alphabet. Venter and his team invented this cryptic alphabetic code so that when they're deciphered, these hidden messages spell the names of the researchers, a series of famous quotes, a web URL, and an explanation of the coding system (5,6).

The potential application of these synthetic bacteria will be limited by only our imagination. Among many promising applications of this technology (ranging from oil spill cleaners to pharmaceutical agents), two of the most encouraging are biofuel producers and cancer destroyers (7).

Biofuel producers

Earth is currently undergoing its sixth mass extinction. C. D. Thomas and his colleagues (2004) predicted that "by 2050, 15 to 37 percent of species [studied] will be committed to extinction" at the present rate of human disruption (8). In an age where our Sasquatch carbon footprint is shouldering the blame for this devastation, finding alternative cheap and sustainable energy sources, such as biofuels, is a priority (9). To date, there are three types of biofuels: first generation, second generation, and third generation. First-generation biofuel is produced from crops and is currently in use. Biodiesel, for example, is commonly used throughout Europe as a substitute for diesel fuel. However, it has several limitations, including cost, efficiency, and the consumption of valuable food supplies during the current world food crisis (10). Second-generation biofuel is produced from non-food crops, reducing the potential for further global food shortages, but still falls short of being a viable alternative fuel. H. Paul and A. Ernsting (2008) warned that using large amounts of biomass (which the second-generation biofuels use) "would almost certainly accelerate biodiversity losses and reduce carbon storage in forests" (11). Wheat yields very high outputs of biomass per hectare, but can it be spared during the current World Food Crisis?

Image Reprinted with Permission from Photographer Julie Kassell, J., 2010. Chippings. [photograph] (Kassell's personal collection)

On the other hand, third-generation (3G) biofuel, which would be produced by synthetic bacteria (as aforementioned), is rapidly developing. Carbon-neutral fuels that emit as much carbon dioxide as they absorb are a promising avenue for genetically-modified organisms. One such group, called microalgae, is currently under extensive study to produce efficient amounts of biofuel for our evermore energy demanding endeavours (12,13). Researchers are currently engineering microalgal cells to possess an enhanced genome that can produce a range of biofuels, including biodiesel, ethanol, and hydrogen. These organisms, the size of a single human hair, produce the fuels using only water, carbon dioxide, sunlight, and industrial waste (which contains the nutrients required by microalgae) (14). An even more ambitious study involving fourth-generation biofuel is now being speculated with carbon-negative organisms. These organisms have more carbon intake than carbon emissions, thereby reducing greenhouse gases and providing cleaner fuels (15). The research is still in its infancy, but it's showing promising results. Clyde Hutchison inspecting a batch of carbon-converting microbes at Venter's Synthetic Genomics.

Source: Jurvetson, S., 2007. Green Tech. [electronic print] Available at:
http://www.flickr.com/photos/44124348109@N01/2126204366/ [accessed 21 August 2008]

Dedicated cancer destroyers

Current cancer treatments indiscriminately attack both tumours and normal tissues, whilst inefficiently penetrating the former (16). As a result, patients are subject to severe side effects and reduced chances of survival. Thankfully, much more effective cancer therapies may soon be realized with the application of synthetic bacteria.

Genetically-engineered E. coli cells would first invade the body without alarming the immune system. Engineered to possess a K-type capsule and specific O antigens, these artificial stealth machines would not be identified as "foreign" and can thus pass through the bloodstream undisturbed (17). The cells would be programmed to find tumour tissues by searching for telltale signs, such as high cell density and anaerobic growth. In order to ensure that bacteria do not invade skeletal muscle during exercise (which can also be anaerobic), the cells would be designed to only invade when both of these conditions are satisfied (18). With their target in sight, the E. coli would implement their destructive force through a "cytotoxic or immunostimulatory response" (Nemunaitis et al, 2003), meaning they would attempt to destroy the tumour tissues by releasing toxic chemicals, or by triggering an immune response. Though the research is still ongoing, the introduction of synthetic bacteria will undoubtedly open the floodgates for the cancer treatment using these engineered microbes (19). A possible immunostimulatory response triggered by the engineered E. coli, causing macrophages to fuse with, and inject their toxins into, the cancer cell.

Source: Arnold, S., Guirguis, R., 1988. Macs killing cancer cell. [photograph] (National Cancer Institute)

Weapons of microscopic destruction

Despite the valuable assets these synthetic organisms can yield, the implications of such technology are sending shockwaves through the scientific community. For all the good deeds mankind could achieve with this stepping stone, it could just as easily be used to springboard equally terrifying agendas, such as bioterrorism and environmental disasters. George Church of the Harvard Medical School has realised its alarming potential, calling for "everybody in the synthetic biology ecosystem [to] be licensed like everybody in the aviation system" (1).

Biological warfare dates back as far as Ancient Rome, when faeces were thrown at the faces of enemies. Nowadays, far deadlier pathogens have replaced human wastes. In fact, the U.S. National Science Advisory Board for Biosecurity was set up to minimize such risks of bioterrorism. All fifty states in the U.S. have now developed bioterrorism plans, identifying pathogens into "Category A, B or C" with "A" being the highest risk (20). As aforementioned, there are concerns throughout the scientific community about the safety of synthetic biology because synthetic biology research makes it possible to manufacture a "Category A*" super-pathogen. Eckard Wimmer, Distinguished Professor in the Department of Molecular Genetics and Microbiology at the State University of New York, sparked a media frenzy in 2002 when his team chemically synthesised the poliovirus (21) from mail-order DNA. Biologists queued up to warn that this was the exact type of research terrorists could use to synthesise viruses such as HIV and Ebola. Undeterred, Wimmer defended his research saying, "We've been criticized for playing into the hands of a bioterrorist, but other groups have already written that this could be done" (22).

The counter argument is that perilous pathogens have been around long before mankind began artificially mixing-and-matching their genes. If terrorists intend to attack, they do not require state-of-the-art laboratories, brilliant researchers, or copious sums of money in order to synthesise and perfect an unstoppable killer. What Mother Nature provides is already deadly enough. Could this warning sign one day become a familiar sight, used to caution onlookers of dangerous renegade species in the area?

Image Reprinted with Permission of Photographer Julie Kassell, 2010. Warning signs. [photograph] (Kassell's personal collection)

Environmental disasters

When contemplating the possible effects that an escaped synthetic microbe may have on the environment, it is easy for one to get carried away. Still, we cannot forget that humans have been introducing new species into different parts of the world for hundreds of years. Whether intentionally or unintentionally, Earth's ecosystem has yet to collapse. In fact, the reality is that any fugitive synthetic organism is likely to be out-competed by their wild-type counterpart, which can boast the benefit of billions of years of evolution.

In addition, researchers could employ numerous safeguards to prevent the spread of lab-prepared creatures. Venter and his team already incorporated one of these safeguards into their "Synthia" creation: the removal of certain genes that make the bacterium pathogenic (5). Furthermore, researchers could engineer the microbes to be biologically dependent on a chemical that is only available in the lab. For example, if bacteria were created to clean up sewage, they would be given this chemical onsite and then starved of it. These sorts of measures would be known as "suicide genes" (23).

However, despite their great improbability, worst-case scenarios could happen if researchers manage to outshine evolution, fail to incorporate any of the above safeguards, and/or are careless enough to allow the synthetic microbe to escape into a suitable environment. The microbe's beneficial artificial genome could help it obliterate native species and colonize extensive terrain. Depending on the bacteria, they may even be lethal for humans. Similarly, with a reproductive cycle as fast as twenty minutes, bacteria evolve rapidly. This may give rise to mutants that allow the renegade organism to survive, even flourish, outside the lab despite the precautions taken. Electron microscope image of the pathogenic species Campylobacter, the number-one cause of food-related gastrointestinal illness in the United States.

Source: De Wood, Pooley, USDA, ARS, EMU, 2008. Campylobacter. [electronic print] Available at: http://www.ars.usda.gov/is/graphics/photos/ [accessed 21 August 2008]

Synthetic biology has the potential to shape the future of Earth and every one of its inhabitants. The 21st Century is writing history this very moment. Humanity must now decide whether it wants to bequeath a mass extinction, or be remembered for stabilizing the climate, curing cancer, and creating life.

References:

1. J. Craig Venter Institute. (2010). First self-replicating synthetic bacterial cell. Available from: http://www.jcvi.org/cms/research/projects/first-self-replicating-synthetic-bacterial-cell/overview/. Last accessed 3 July 2010.

2.Science Media Centre. (2010). Experts on Craig Venter's synthetic biology breakthrough. Available from: http://www.sciencemediacentre.co.nz/2010/05/21/experts-on-craig-venters-synthetic-biology-breakthrough/. Last accessed 20 August 2010.

3. Aaron Saenz. (2010). Venter Creates First Self-Replicating Bacteria From Scratch. Available from: http://singularityhub.com/2010/05/20/venter-creates-first-synthetic-self-replicating-bacteria-from-scratch/. Last accessed 2 July 2010.

4. Gibson, D.G. et al. (2010). Creation of a Bacterial Cell Controlled by a Chemically Synthesized Genome. Science. 329 (5987), 52-56.

5. Aaron Saenz. (2010). Secret Messages Coded into DNA of Venter Synthetic Bacteria. Available from: http://singularityhub.com/2010/05/24/venters-newest-synthetic-bacteria-has-secret-messages-coded-in-its-dna/. Last accessed 18 August 2010.

6. Fiona Macrae. 2010. Scientist accused of playing God after creating artificial life by making designer microbe from scratch - but could it wipe out humanity? Available from: http://www.dailymail.co.uk/sciencetech/article-1279988/Artificial-life-created-Craig-Venter--wipe-humanity.html. Last accessed: 4 July 2010.

7. European Commission. (2005). Synthetic Biology: Applying Engineering to Biology. Available from: ftp://ftp.cordis.europa.eu/pub/nest/docs/syntheticbiology_b5_eur21796_en.pdf. Last accessed: 2 July 2010.

8. Thomas, C.D. et al. (2004) Extinction risk from climate change. Nature. 427 (6970), 145-148.

9. Solomon, S. et al. (2007). Contribution of Working Group I to the Fourth Assessment Report of the Intergovernmental Panel on Climate Change. Available from: http://www.ipcc-wg1.unibe.ch/publications/wg1-ar4/wg1-ar4.html. Last accessed: 4 July 2010.

10. Organisation for Economic Cooperation and Development. (2008). Biofuel Policies in OECD Countries Costly and Ineffective, Says Report. Available from: http://www.oecd.org/document/28/0,3343,en_2649_37401_41013916_1_1_1_1,00.html. Last accessed: 1 July 2010.

11. Paul, H. and Ernsting, A. (2008). Second Generation Biofuels: An Unproven Future Technology with Unknown Risks. Available from: http://www.biofuelwatch.org.uk/inf_paper_2g-bfs.pdf. Last accessed: 2 July 2010.

12. Renewable Energy Resource. (Unknown date). Fourth Generation Biofuels. Available from: http://renewableenergyresource.net/renewable-energy-sources/fourth-generation-biofuels. Last accessed: 4 July 2010.

13. Beer, L.L. et al. (2009). Engineering Algae for Biohydrogen and Biofuel Production. Current Opinion in Biotechnology. 20 (3), 264-271.

14. Costa, J.A.V. and De Morais, M.G. (2010) The Role of Biochemical Engineering in the Production of Biofuels From Microalgae. Bioresource Technology. Article in Press.

15. Biofuel Review. (2008). Fourth Generation Biofuels Mooted By UK Researchers. Available from: http://www.biofuelreview.com/content/view/1493/. Last accessed: 1 July 2010.

16. St Jean, A.T., Zhang, M., Forbes, N.S. (2008). Bacterial Therapies: Completing the Cancer Treatment Toolbox. Current Opinion in Biotechnology. 19 (5), 511-517

17. Burns, S.M., Hull, S.I. (1999). Loss of Resistance To Ingestion and Phagocytic Killing By O- and K- Mutants of a Uropathogenic Escherichia coli O75:K5 strain. Infection and Immunity. 67 (8), 3757-3762

18. Anderson, J.C. et al. (2006). Environmentally Controlled Invasion of Cancer Cells by Engineered Bacteria. Journal of Molecular Biology. 355 (4), 619-627

19. Nemunaitis J., et al. (2003). Pilot Trial of Genetically Modified, Attenuated Salmonella Expressing Cytosine Deaminase Gene in Refractory Cancer Patients. Cancer Gene Therapy. 10, 737-744.

20. American Public Health Association. (Unknown date). Bioterrorism Preparedness. Available from: http://www.getreadyforflu.org/Bioterrorismonlinefactsheet.pdf. Last accessed 4 July 2010.

21. Cello, J., Paul, A.V., Wimmer, E. (2002). Chemical Synthesis of Poliovirus cDNA: Generation of Infectious Virus in the Absence of Natural Template. Science. 297 (5583), 1016-1018

22. Check, E. (2002). Poliovirus Advance Sparks Fears of Data Curbs. Nature. 418 (6895), 265

23. National Research Council (U.S.). Committee on Biological Confinement of Genetically Engineered Organisms (2004).Biological confinement of genetically engineered organisms. Washington: The National Academies Press. 169-179.

Author: Danny Watts, King's College, London, England

Science Writing Mentor: Selby Cull

Further reviewed by: Phuongmai Truong, Karuna Meda, Natasha Hochlowski, and Yangguang Ou

Published by Maria Huang

JYI has a peer-review process through which undergraduate research editors work with faculty mentors at their institutions to determine the validity of journal submissions. This process closely mimics those found in other professional research journals.
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