More by the microscopic than the colossal
Fong Khi Yung, Raffles Institution
On some evenings, I walk through the expressionless countryside fields undulating in the wind, gazing up at the crimson heavens and golden sunset sending warm rays through the clouds.
Night soon falls, the faceless sky paying tribute to the boundless infinity of space; but it is merely a façade. What appear as microscopic dots in a sky full of stars, can be the force that sweeps mankind off its knees.
Centuries ago an acclaimed novel was written. War of the Worlds, by H. G. Wells; the fictional story of invading Martians who eventually died from earthly bacterial infections.
It was fiction…until recently.
Modern civilization was unprepared to fight the Martians, who literally descended from the sky and wielded all kinds of unheard-of weapons. Man succumbed to an era of colonization.
Learning from their history, the Martians had invented antibiotics before their mission, and went about pillaging Earth without much worry. Yet their joy was short-lived: antibiotic resistance was almost complete on Earth, but not theirs; it kept them hamstrung as they rampaged. Colistin resistance neared 100%; MRSA and TB were now killing Martians aside from humans.
The determined Martians started recruiting human help to solve their problem. Having mastered our language, they rounded us microbiologists up and conveyed to us that we were to be offered jobs. (The alternative was death by heat-ray). We were to head the war on bacteria in our post-antibiotic era.
The Martians must’ve fancied body suits, for they set us work on creating bacteria-repellent surfaces.
Dragonfly wings are an example of natural nano-textured surfaces. Under high-power microscopy, they resemble a bed of nails. Bacteria landing on the wings contact the nanopillars, which puncture holes in their cell walls. If surviving bacteria attempt to move, shear forces arising from contact between nanopillars and bacterial capsule can rupture them. Surfaces of nano-silicon modelling the ‘bed of nails’ have been tested. Taking a futuristic view, these surfaces could coat the insides of catheters to prevent biofilm formation and prevent opportunistic infection1. They could also be used to coat human skin in areas of high bacterial infestation, preventing infection through the subcutaneous pathway.
Fusing our nano-silicon coating with human skin was easy, but since Martian skin was more jellylike than humans’, the idea didn’t stick particularly well, literally and figuratively, with them. We were soon forced back to work.
Scientists have already employed plants to fight the war against bacteria. Plants produce their own compounds such as flavonols and alkaloids in response to bacterial infections2. Purposely infecting plants and fungi with bacteria could induce them to produce antibacterial compounds against specific strains.
On that note, scientists could attempt to train harmless natural predators of bacteria3, such as the eukaryote Paramecium, to target specific strains of bacteria for engulfment. As these predators are blood-mobile, our immune systems must first be desensitized to them via gene therapy. When the infection is cleared, antiparasitic drugs can be administered to rid oneself of the paramecia.
We weren’t too optimistic about using plants and fungi as drug factories. Most antibiotics from this method soon joined their predecessors in the depths of obsolescence.
Experimenting with free-living bacterial predators went better. It worked for two years till realized that bacteria began to evade their captors, just as they’d learned to dodge Martian immune systems.
We were put back to work again. Never mind that many had died insane or, ironically, from research-acquired infections.
Discontent was brewing.
Most traditional biochemical remedies against bacteria disrupt biomolecule synthesis, be it of membranes, DNA or proteins. Thus, antibiotics act as a form of artificial selection. Bacteria which gain antibiotic-resistance mutations in their genes or plasmids have a selective advantage, and survive to pass on their DNA. Soon, most bacteria are resistant. Antibiotics may even exacerbate resistance by triggering a chemical ‘SOS signal’, RecA, that ramps up the bacterial repair machinery and encourages horizontal gene transfer through conjugation with other bacteria.
Studies show that turning off the RecA enzyme may stop repair and conjugation, allowing antibiotics to remain effective for longer time periods4. Extrapolating, gene editing techniques like CRISPR-Cas3 may allow us to target bacterial genes that code for self-defense, and silence them5. This would essentially reverse existing resistance and freeze the evolution of resistance long enough for antibiotics to work.
More radical methods have also been put forth as cures for resistant microorganisms.
Bacteriophages, currently in small-scale usage, infect and lyse specific bacterial species by recognizing receptors on their cell walls. The exponential growth characteristic of viruses helps to clear bacterial infections rapidly, eliminating the need for frequent treatments 6. However, this risks the possibility of mutations in bacterial surface proteins that desensitize a strain to phage infections. It would be a high-turnover process to engineer new effective phages as old ones become obsolete.
Ambitious extrapolation of the above idea leads us to nanobots. Purely hypothetical for now, nanobots are the size of ribosomes, moving freely through tissues. We can attach nano-sensors to nanobots that detect the presence of harmful bacteria by chemical means. When detected, nanobots then physically puncture holes in the bacteria. A mechanized, computer-programmed war machine is impossible to develop resistance to. This in contrast to bacteriophages, which require target bacteria to accept the viral genome unsuspectingly.
Backing up all ideas is the notion of stimulating bodily defenses. Used in CART therapy, giving naïve immune cells receptors to an antigen causes the body to mount defenses, secreting interleukins and inflammatory mediators to encourage immune surveillance7. With an understanding of the enemy, effective antibody production via clonal selection can occur. Nanobots could, for example, follow chemokines left by activated macrophages to sites of infection, and themselves release chemokines at the site. This allows the immune system to complement a wide range of antibacterial technologies.
Traditional antibiotics exhibit side effects because the bacterial structures they target may resemble ours. Similarly, free-living bacterial predators can themselves turn infectious. Bacteriophages can induce inflammatory responses in the host. And nanobots risk colossal inflammatory damage if their receptors are triggered by normal microflora.
The solution to a post-antibiotic world brimming with new technologies is optimization, just as with antibiotics. Our targeting of bacterial biomolecules has forced us into an endless hide-and-seek battle with evolution. Unintuitively, by administering drugs to help stabilize the bacterial genome instead of triggering a mutation, we can halt their evolution enough to give us a free hand on what to target within them. ‘Smart’ algorithms can also be used to predict the structures of mutated biomolecules and distinguish pathogenic bacteria, allowing nanobots and their drugs to be flexible in specificity.
After an age of antibiotics, innovative ideas that involve physics, computing, other organisms and our immune armies need to be tested. By ensuring their specificity and sustainability, we could potentially turn the tide of the war on bacteria.
We eventually pioneered a regimen combining freezing of bacterial evolution and targeting lipopolysaccharides with nanobot therapy. Our captors grasped feverishly at the prospects of a cure, inoculating themselves with anything rumored to work. They could not but trust us – their technological prowess sure was formidable, yet they lagged humanity by a decade in the study of the smallest living creatures.
Martian cells are mostly identical to ours, except for neurons. Neuro-receptors in the prefrontal cortex, controlling personality, were discovered to be identical to those in pathogenic bacteria. And nanobots could be programmed to destroy anything that bound to their receptors.
Our chance had arrived.
Sure, our nanobots and phages killed the bacteria. But it killed more than that.
Think of shattered shells of what used to be a Martian; physically functioning and retaining past memories, but zombie-like, mentally detached from living.
The Martians were taught yet another valuable lesson: in a post-antibiotic world, ensuring the specificity and sustainability of treatment is perhaps just as important as innovating new cures. Whether or not Mars learns from this, mankind definitely must.
I retired to the countryside, removed from the horrors of a slowly rebuilding civilization. Monthly packages arrive with body-cleansing nanobots, which I swallow to keep pathogens away. Once a year, I visit the city for genetic screening. If mutated DNA arises in normal flora, phage therapy follows.
It was recently reported that mankind had, with impulsive vengeance, declared war on Mars. It was also reported, with almost forced nonchalance, that an aggressive viral strain would replace certain obsolete bacteriophages.
The war on bacteria, much like that with Mars, is far from over.
For now, I live in the outskirts of an Earth shattered uncountable times, more by the microscopic than the colossal. On some evenings, I walk through the expressionless countryside fields undulating in the wind, gazing up at the crimson heavens and golden sunset sending warm rays through the clouds.
I wait till it’s dark to admire the stars, numerous and expansive as the bacteria that once ravaged us, yet are here to stay till kingdom come.
1Nanopillar coatings: http://www.acsh.org/news/2016/08/09/bed-of-nails-surface-physically-rips-bacteria-apart
2Medicinal plant compounds: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC88925/
3Predatory antimicrobials: http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0063397
4SOS response and RecA enzyme: http://www.cell.com/cell-chemical-biology/fulltext/S2451-9456(16)30046-0
5CRISPR-Cas3 antibacterial gene therapy: http://www.ncbiotech.org/article/locus-biosciences-lifts-lid-crafty-crispr-bust-bad-bacteria/211541
6Phage therapy: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC90351/
7Immunotherapy combined with antimicrobials: http://aac.asm.org/content/54/5/1785.full