In 1953, molecular biologists James Watson and Francis Crick released what would be one of the most groundbreaking scientific discoveries of the modern age. The publication of their research paper Molecular Structure of Nucleic Acids: A Structure for Deoxyribose Nucleic Acid in the scientific journal Nature marked the end of a heated race to find the molecular structure of DNA, marking the dawn of molecular genetics. But neither man (nor their then-uncredited co-discoverers Rosalind Franklin and Raymond Gosling) could have envisioned how their work would permeate into every facet of modern society, including pop culture.

“No gods or kings. Only man.”

These are the words that greeted players to the underwater city of Rapture in the 2007 video game BioShock. Founded on the objectivist philosophies of entrepreneur Andrew Ryan, the city was intended as a haven for the world's greatest free-thinking minds. Free from the “oppressions” of politics, religion, and society, the citizens of Rapture could indulge in their artistic, scientific, and commercial pursuits.

The absence of ethical, legal, and sociological barriers within Rapture, combined with the discovery of the infamous genetic manipulator ADAM, resulted in the premature birth and prolific advancement of molecular genetics. The ADAM serum—a stem-cell-rich excretion of a previously undocumented sea slug—had the uncanny ability to replace or regenerate human cells and tissues.

Further Reading A different kind of Rapture: a review of Bioshock

Above sea level, the discovery of a panacea such as ADAM could have ushered in a new era of medical wonderment. Rapture's libertarian founding philosophies, however, led to the development of a range of super power-granting “plasmids.” With the right plasmids and enough ADAM, players and citizens alike could wield lightning, fire, and ice through their fingertips, use telekinesis and hypnosis, and even turn invisible.

The upcoming BioShock Infinite downloadable content, titled Burial at Sea Episode Two, will offer players a chance to return to Rapture during the heyday of heavy plasmid use, and it will likely re-captivate many players with the fanciful idea of externally administered genetic “power-ups.” But the ideas behind this scenario aren’t entirely confined to the realm of science fiction. In fact, the latest scientific literature suggests that human genetic modification through real-life plasmids may be possible in the near future.

Non-BioShock plasmids

In real life, plasmids are small loops of DNA found within bacteria, existing independently of the core bacterial chromosome and containing far fewer genes. As with BioShock's plasmids, different bacterial plasmids grant different traits to their bearers and can be passed from organism to organism via a process called horizontal gene transfer.

To clarify, genes transferred vertically are passed from one generation to the next—from parent to child. Genes transferred horizontally can be passed between organisms of differing generations and even species. This act of cross-organism gene transfer wasn't thought possible prior to the work of American molecular biologists Edward Tatum and Joshua Lederberg in the 1940s.

Tatum and Lederberg's discovery was made following observations of a mixed culture of two E. coli strains with complementary metabolic deficiencies. In these cultures, a third strain, capable of surviving without nutrient supplements, would arise. It was known at that time that E. coli did not mate sexually—like all bacteria, it reproduces asexually, dividing into like-for-like copies through binary fission. But Tatum and Lederberg hypothesized that the third strain came about because genetic material was being “shared” on contact.

The two biologists also proposed that there was a “fertility factor” that allowed for the genetic exchange. But it wasn't until the dawn of molecular genetics that the fertility factor was found to be a circular loop of DNA that existed independently of the bacterial genome—a plasmid.

Renamed the F-plasmid, the short sequence of DNA contains all the genes necessary for a bacterium to form a pilus—a long, thin, tentacle-like protrusion—and attach itself to another bacterium lacking F-plasmid. The pilus reels in the donor bacteria, and a copy of the F-plasmid, along with the bacterial chromosome, is transferred into it horizontally. This process is known as conjugation.

But conjugation is not F-plasmid's only trick. Infrequent cellular mishaps can cause an F-plasmid to accidentally integrate into the main bacterial chromosome. If and when it's excised by the cell, the F-plasmid often takes adjacent DNA along with it, including entire genes. F-plasmid derivatives known as R-factors, for example, contain an additional suite of antibiotic resistance genes. Other transferable traits could include toxin production, viral resistance, enhanced longevity, and more.

As interesting as the plasmids themselves are, what's more interesting is how they can be manipulated for use in genetic research. By artificially inserting non-bacterial genes into an F-plasmid and introducing them to a bacterial culture, the foreign genes can be amplified through horizontal and vertical transfer, and the gene can be studied in a simple bacterial environment.

These artificial bacterial plasmids are now routinely used for the study of bacterial and non-bacterial gene function and the cloning and sequencing of DNA—the Human Genome Project relied on them. Genetically modified bacteria also offer a cheap and efficient source of human insulin, crop pesticides, and soil fertilizers. These have been used industrially for decades.

One genus of bacteria, Agrobacterium, takes conjugation one step further by horizontally transferring plasmids directly into the genome of plants. Agrobacteria were well-known to researchers in both agriculture and science, who have studied them for over 100 years because they trigger crown-gall disease—a plant ailment that results in the growth of root tumors.

But it wasn't until the 1940s that Armin Braun, of the then-Rockefeller Institute for Medical Research, suggested the transfer of a genetic “tumor inducing principle” between Agrobacterium and plant. At the time, Braun's idea came from his observation that the aforementioned plant tumors did not contain a significant volume of Agrobacterium. Now, the molecular basis of Braun's elusive principle is known as the Ti (tumor inducing) plasmid.

Upon detection of an open plant wound, Agrobacteria attach themselves to an internal plant cell and inject a copy of the Ti-plasmid into it. The Ti-plasmid genes are then read by the host cell's cellular machinery, which is instructed to integrate Ti-plasmid genes directly into the plant genome.

From there, the host cell reads the Ti-plasmid genes, which include various plant growth hormones, resulting in rapid plant cell proliferation and the formation of tumors—tumors that, under instruction from the integrated Ti-plasmid, produce nitrogen-rich molecules as a food source for the surrounding Agrobacteria.

As a proficient genetic hacker, Agrobacteria—and the species Agrobacterium tumefaciens in particular—have become the plant biologist's tool of choice. Just like the aforementioned F-plasmid modifications, the Ti-plasmid can be altered to include any gene of interest. It's this technology and others like it that have led to the creation of genetically modified plant seeds with added pesticide production, salt tolerance, nutritional value, and more, such as The Golden Rice Project.

The intrigue surrounding Agrobacteria doesn't even stop there. More recent studies have shown that under strict laboratory conditions, Agrobacteria can be encouraged to transmit Ti-plasmid into yeast cells, fungal cells, algae cells, and even cultured human cells.

Still, for better or worse, on-demand, bacterial-plasmid-mediated alterations of entire human genomes is nothing but science fiction with current technologies. But a real-world equivalent to BioShock's plasmids may lie elsewhere—the simple yet powerful virus.

Viral for good

Nature's true minimalists, viruses are often described as being at the “edge of life.” Consisting only of a small amount of genetic material encased in a protein coat—and an additional bubble of oil if it's particularly fancy—viruses do not eat, breathe, or excrete any exogenous matter whatsoever. Viruses are, however, expert genetic hackers that exist for one simple purpose—replication. Viral genetic material, like bacterial plasmids, is incredibly succinct, containing only the genes necessary for this purpose.

After a virus gains entry to a cell—human or otherwise—the viral coating breaks down, leaving its genetic material exposed. In many cases, these viral genes program the host cell to assemble new viruses until the cell quite literally bursts. But there’s a group of animal-infecting viruses called retroviruses that like to do things a bit differently. Instead of manipulating host cells to construct new viruses upon infection, retroviruses integrate their genetic material directly into the host's genome, where it can lie dormant for many years before becoming active—as is the case with HIV.

On rare occasions, retroviruses infect germline cells—which can, on even rarer occasions, give rise to offspring containing a copy of the retroviral DNA within every cell of its body. It's at this point that the virus becomes what is known as an endogenous retrovirus (ERV). Although our ancestors evolved systems to deactivate most ERV genes, history shows that we're not half as good at removing them from our genomes. As such, current estimates put ERVs at five to eight percent of our total genomic DNA, a significant proportion of which have been present in our evolutionary timeline for millions of years.

Their simplicity, combined with the relative ease with which they enter cells and control the cells’ DNA (or, in the case of retroviruses, permanently alter their DNA) has made viruses an extremely useful tool in genetic research. For example, researchers can replace virus genes with a gene of scientific interest, creating a virus that can safely and efficiently transform cell cultures. The cell specificity of many viruses also allows scientists to target a specific tissue of a particular species—a trait that has been exploited in gene therapy.

Despite their scientific utility, discussions continue to this day over whether viruses deserve a place within the realm of living organisms. It may be surprising to some that inheritance—a basic feature of the living—is exhibited in genetic entities even simpler than viruses.

Transposable elements, or “transposons,” are short lengths of DNA that are able to move from one location in a genome to another. Unlike a virus, however, transposons never leave the cell they started in. Like ERVs, transposons have inhabited our DNA for millions of years, and parts of transposons comprise almost a half of the human genome. This makes transposons (and ERVs) ideal for tracing back evolutionary lines and identifying speciation events.

Transposons Transposons are mobile genetic elements, pieces of DNA that can relocate within the genome, an ability that earned them the nickname "jumping genes." They are extremely common in many species, where they often constitute a large fraction of the genome. A single type of transposon called the Alu element, for example, accounts for 13 percent of the human genome. Read more…

Each of us contains within our genomes thousands of different transposons—the vast majority of which have been rendered inactive by mutations—but active transposons can still spell trouble for our cells.

Transposons are often mutagenic: they can turn a gene off by inserting themselves into it, reactivate a gene by exiting it, or alter a gene's rate of expression by inserting themselves into regulatory sequences. Additionally, transposons can leave irreparable gaps in their wake, cause DNA repeats to build up, and even form new and unwanted genes. In most cases, the problems caused by transposons will only affect the DNA of individual cells—typically, the DNA is repaired by the cell or, failing that, can result in programmed cell death. Even so, transposons have been implicated in a number of diseases, including haemophilia, cystic fibrosis, Apert syndrome, various cancers, and more.

Although these selfish DNA parasites impart no obvious benefits to their multicellular hosts, the bacteria-transposon relationship is much stronger. Many bacterial transposons carry antibiotic resistance genes and other advantageous traits between a bacterium's genome and its plasmids, hastening the spread of these traits throughout a population. Just like the aforementioned bacterial F-plasmid and Ti-plasmid, the exploitation of transposons' unique abilities by scientists has offered another excellent genetic tool.

For example, a transposon containing an easily identifiable genetic sequence can be introduced into a bacterial colony. The colony can then be monitored for any noteworthy characteristics, such as altered metabolism, which is caused by the random insertion of the transposon into a bacterial genome—a process known as insertional mutagenesis. Once isolated, the bacteria's genome can be scanned to locate the unique transposon sequence, thus revealing its location and thereby the location of the gene responsible for the interesting characteristic.

Taking the process one step further, a transposon can be modified to contain a marker gene such as GFP (green fluorescent protein). This simplifies the identification and isolation of engineered bacterial genomes, as cells containing the transposon will glow green under ultraviolet light. Similar techniques are also used to perform transposon insertional mutagenesis screens for genes in fruit flies, zebrafish, rice plants, mice, and even cultured human cells.

Knowing all this, the idea of BioShock-style plasmids seems a bit less far-fetched. Let’s say for a moment that the world's greatest scientific minds somehow concocted a reliable transposon vector for use with live, fully grown humans. Let’s then say that multiple different concoctions were created, each featuring a different fantastical transposon that itself contained a weird and wonderful gene unlike anything seen on this Earth. Let’s go one step further and say that these serums were produced en masse for exclusive use by the citizens of an intellectually unbounded underwater city...

You get the (hypothetically plausible) picture.