Note to the reader: this text was originally written as DNA sequences, and therefore any information might have been lost in translation.
Hi there,
I am inside of a test tube waiting for the next experiment to begin. Whilst the scientist is busy preparing all the reagents required, I found myself thinking of the long journey that humans and microbes have had. I decided to write this letter to show you how far we have come and what new exciting journeys await us in the future.
My name is Escherichia coli K-12, but you can just call me E. coli. Because I’m not harmful (unlike my close siblings) I have been domesticated and referred by scientists as ‘’lab strain’’. I have been studied as early as 1885(1), and my genome was fully sequenced in 1997(1). I am the most well-studied organism on this planet; isn’t it funny that humans know more about me than they know about themselves?
There are more than 5000000000000000000000000000000, that’s right, five million trillion trillion of us in the world(2), but only about 10% can hurt you, animals and plants. Because of those hazardous family members, humans seem to be afraid of us, when ironically, there are more of us in their bodies than their own human cells(2). But, despite the undeserved bad reputation, I think scientists have realized that most of us are actually good for your health(3). For example, there is a whole variety of my cousins living in human’s gut. We help the immune system stay alert against other micro-invaders by stimulating antibody production, and we also fight any other pathogens that attempt to claim our gut territory. We protect humans and help them stay healthy(4).
Besides being your gut’s bodyguards, we send signaling molecules to your brain through the nervous tissues in the gut to regulate the brain’s chemistry and help in stress response, anxiety and memory function(3). If that wasn’t enough, we also help your digestive system by breaking down the food for better absorption, and as a gesture of gratitude, for giving us a cosy home with unlimited food, we produce vitamins for you.
The richness and variety of the nutrients that you consume determine our diversity, and any significant alteration in our abundance in the gut is linked to allergies, depression and diseases such as Alzheimer’s and autoimmune disorders(5). Some of these benefits have been known for thousands of years well before humans knew about our existence(6). The Ancient Chinese, for instance, have been unknowingly using us to treat diseases by transplanting bacteria-rich faeces from healthy individuals to ill individuals for more than 4,000 years(6,7).
Another example is what is now known as food biotechnology. Born in the Neolithic age as a preservation method, the fermentation of vegetables, fruits, grains and milk soon became a common practice(8). The food was easier to digest, it kept for longer, and more importantly, carried fewer risks of causing food poisoning. Fermentation is a process in which my relatives, such as Lactobacillus, feed on the sugars available and produce lactic acid, the compound that acts as a preservative and gives the sour taste.
Humans’ curiosity with fermentation later led to the development of the brewing process, which produces a compound you have loved for centuries: alcohol. Besides providing the pleasing light-headedness effect, ancient alcoholic beverages were also a source of nutrients – as my distant cousins’, yeast, can produce a range of vitamin B such as folic acid, riboflavin and thiamine(9,10). Humans have been mastering this process for over 9,000 years(11). Indeed, a series of descriptions of early beers were found in Ancient Egypt records from the 3rd century AD(12). Nowadays, beer, wine, yogurt, cheese and many other microorganism-dependent foods are heavily consumed worldwide. All thanks to humans’ ability to manipulate us, and most importantly, our hard work.
Even though the first ‘’animalcule’’ (the original name given to us, meaning ‘tiny animal’ in Latin) was described in 1676 by the Dutch scientist Antonie Van Leeuwenhoek(13), the domestication of microbes only occurred in the late 1900s, when humans began culturing us and discovering our natural abilities.
In the early 1930s, scientists found that microbes naturally produce chemicals as a defence mechanism to fight other microorganisms – just like humans use weapons to protect themselves or to conquer territories. These chemicals were labelled as antibiotics (derived from Greek, anti = opposed to, biotics = life); the first antibiotic found was penicillin discovered by Alexander Flemming(14). From that discovery, scientists started extracting natural antibiotics from soil bacteria; and making it into pills to fight nasty bacterial infections, where human immune system couldn’t.
The thing is: antibiotics are not specific, so they kill almost all bacteria that they encounter, including the friendly ones in your gut. I said ‘almost’ because genetic mutations may arise. This gives us the ability to break down the antibiotics, allowing our survival. The mutated cells are very good in sharing the newly acquired genetic advantage with the rest of the population by passing it along to neighbouring bacteria and also by reproducing - ensuring all future generations have the same mutation. This evolutionary-driven process is known as natural selection.
Most bacterial infections are becoming resistant to all available antibiotics(2), creating a world health crisis. Did you know that scientists haven’t discovered a new antibiotic in the past 40 years? As the search for new antibiotics continues, the next best bet is my marine cousins15! Little is known about these aquatic fellows and they probably have some interesting abilities that humans are unaware of.
Similarly to following recipes to cook a specific dish, DNA sequences are the biological cookbook consisting of a set of instructions to make proteins and chemical molecules. Scientists recently realised that we, E. coli, can produce anything as long as the right DNA sequence is given to us (this is the equivalent of being gifted with the latest Gordon Ramsey’s book, with the recipe for the perfect chocolate cake). They have been testing and mastering this process for many years(16).
I have personally made bioplastics, biofuel, pharmaceuticals, biopesticides, vitamins, hormones, proteins, and many other small, organic compounds(17,18). The potential products are almost limitless! In the past century, societies have been obtaining these products through chemical synthesis. This traditional method is deteriorating the planet due to the exhaustion of natural resources, such as coal and natural gas, as well as the pollution produced that is catalysing climate change. Furthermore, to produce certain pharmaceutical products, the catalysts used are often toxic heavy metals that need further purification to be safe for human consumption(19).
That’s why they are looking for new alternatives, and it seems they found one: us! Scientists all around the world are looking for ways to transform us into living factories and use us to produce everything that humans consume through genetic manipulation. Think of us as tiny 3D printers making organic and biological products. We find ourselves in this situation because we can reproduce every 30 minutes, creating an ideal time frame to scale mass production(20). We are easy to grow, eco-friendly, cost-effective, and there is almost no ethical debate involved in manipulating us. We are the perfect candidates to replace the chemical synthesis industry.
I will give you an example. In the 1920s, insulin was obtained from bovine or porcine pancreas. Because of the ethical implications of dealing with animal organs and the low-yield extraction process, insulin was very expensive. But once scientists introduced the right genes in our DNA, we started producing human insulin(21). Since then, we have saved millions of lives because of the insulin we produce!
There is a catch though. The biggest challenge for the biological era is low yield. This process of genetic engineering us to produce something does not provide any survival advantage, which means we can only produce so little of it. Increasing the yield is the key to revolutionize the world as much as the chemical synthesis did in the 19th century(22).
These genetic manipulations led to the field of metabolic engineering, a branch of synthetic biology(23), where they have been applying computational models and engineering concepts to optimize our genetic makeup to improve the yields of the desired chemical. Only over a decade old, this multidisciplinary field has grown considerably, building expectations of being able to address some of humanity’s global health and environmental challenges, and to deliver innovation for economic growth(24).
Hopefully one day we will become biofactories, intertwining the history of bacteria and humans even further.
Long live the biological revolution!
Yours sincerely,
E. coli K-12
By Camila Gaspar
instagram & twitter: @biochemila
linkedin: camila-gaspar-quinonez
contact info: camilaqgaspar@gmail.com
Camila is a biochemist with a master's in systems and synthetic biology and is soon to complete her Ph.D in London. Her multidisciplinary Ph.D research is on developing new drugs to treat tuberculosis by targeting a crucial enzyme in Mycobacterium tuberculosis’ metabolism. She also investigates how the bacteria become drug tolerant to current antibiotics. Last year she was invited by her collaborators at the University of Southern California (USC) to spend the year working in their lab. She loved the warm weather and the beautiful hikes in California, and as a bonus, she found another passion other than science: muay thai. Science communication has always been part of her career: volunteering as an event ambassador at the Science Museum, organising monthly 'PubhD talks' showcasing Ph.D. research in pubs (twitter: @pubhdlondon), and judging school science projects at the Big Bang competition – the largest STEM event for aspiring scientists. During the lockdown, she started the #knowledgeholics project to communicate science through infographics on her Instagram. She is always looking for collaborators, so get in touch!
References:
1. Blattner, F. R. et al. The complete genome sequence of Escherichia coli K-12. Science (1997) doi:10.1126/science.277.5331.1453.
2. Gallagher, J. More Than Half Your Body Is Not Human. BBC News https://www.bbc.co.uk/news/health-43674270 (2018).
3. Durack, J. & Lynch, S. V. The gut microbiome: Relationships with disease and opportunities for therapy. Journal of Experimental Medicine (2019) doi:10.1084/jem.20180448.
4. Hills, R. D. et al. Gut microbiome: Profound implications for diet and disease. Nutrients (2019) doi:10.3390/nu11071613.
5. Fung, T. C., Olson, C. A. & Hsiao, E. Y. Interactions between the microbiota, immune and nervous systems in health and disease. Nature Neuroscience (2017) doi:10.1038/nn.4476.
6. Evrensel, A. & Ceylan, M. E. Fecal microbiota transplantation and its usage in neuropsychiatric disorders. Clinical Psychopharmacology and Neuroscience (2016) doi:10.9758/cpn.2016.14.3.231.
7. Valiquette, L. and Laupland, K. Something Old, Something New, Something Borrowed... Can. J. Infect. Dis. Med. Microbiol. 24, 63–64 (2013).
8. eatCultured. Fermentation: A History. eatCultured https://eatcultured.com/blogs/our-awesome-blog/fermentation-a-history (2017).
9. Meussdoerffer, F. G. A Comprehensive History of Beer Brewing. in Handbook of Brewing: Processes, Technology, Markets (2009). doi:10.1002/9783527623488.ch1.
10. Mayer O., J., Šimon, J. & Rosolová, H. A population study of the influence of beer consumption on folate and homocysteine concentrations. Eur. J. Clin. Nutr. (2001) doi:10.1038/sj.ejcn.1601191.
11. Oliver, G. The history of beer. Craft Beer and Brewing https://beerandbrewing.com/dictionary/UqfrcsPoAI/.
12. Mark, J. J. Beer in Ancient Egypt. Ancient History Enciclopedia https://www.ancient.eu/article/1033/beer-in-ancient-egypt/ (2017).
13. Lane, N. The unseen World: Reflections on Leeuwenhoek (1677) ‘Concerning little animals’. Philosophical Transactions of the Royal Society B: Biological Sciences (2015) doi:10.1098/rstb.2014.0344.
14. Clardy, J., Fischbach, M. A. & Currie, C. R. The natural history of antibiotics. Current Biology (2009) doi:10.1016/j.cub.2009.04.001.
15. Wiese, J. & Imhoff, J. F. Marine bacteria and fungi as promising source for new antibiotics. Drug Development Research (2019) doi:10.1002/ddr.21482.
16. Evens, R. & Kaitin, K. The evolution of biotechnology and its impact on health care. Health Aff. (2015) doi:10.1377/hlthaff.2014.1023.
17. Yi-Heng Percival Zhang, J. S. & Y. M. Biomanufacturing: history and perspective. J. Ind. Microbiol. Biotechnol. 44, 773–784 (2017).
18. Cameron, D. E., Bashor, C. J. & Collins, J. J. A brief history of synthetic biology. Nat. Rev. Microbiol. 12, 381–90 (2014).
19. Schopp, N. Heavy Metals in Drug Products. Contract Pharma https://www.contractpharma.com/issues/2015-01-01/view_features/heavy-metals-in-drug-products/ (2015).
20. Idalia, V.-M. N. & Bernardo, F. Escherichia coli as a Model Organism and Its Application in Biotechnology. in Escherichia coli - Recent Advances on Physiology, Pathogenesis and Biotechnological Applications (2017). doi:10.5772/67306.
21. Baeshen, N. A. et al. Cell factories for insulin production. Microb. Cell Fact. (2014) doi:10.1186/s12934-014-0141-0.
22. Clarke, L. J. & Kitney, R. I. Synthetic biology in the UK – An outline of plans and progress. Synthetic and Systems Biotechnology (2016) doi:10.1016/j.synbio.2016.09.003.
23. Keasling, J. D. Synthetic biology and the development of tools for metabolic engineering. Metab. Eng. 14, 189–195 (2012).
24. Flores Bueso, Y. & Tangney, M. Synthetic Biology in the Driving Seat of the Bioeconomy. Trends in Biotechnology (2017) doi:10.1016/j.tibtech.2017.02.002.
Comentarios