Synthetic success

That's not to say that customized transposons are limited to the hypothetical. A synthetic “Sleeping Beauty” transposon system is already set to be the world's most inexpensive form of gene therapy. But transposons have size limitations that, more than anything, reduce their usefulness in medicine.

Contrary to popular belief, a gene is not a single, autonomous unit. Instead, it's a group of distinct “modules” functioning as one. For example, all genes are proceeded by a “promoter” sequence that allows the gene to be read by the cell. Promoters are commonly joined to activator and repressor sites, allowing the rate of gene expression to be controlled. Many genes in plants and animals also contain numerous sections that can be read or skipped by the cell in a process known as alternative splicing, where one gene can contain the code for more than one protein. To make matters even more complicated, regulatory DNA sequences can be responsible for the expression of several adjacent genes—in bacteria, this unit is known as an operon.

Transposons are useful when working with relatively small pieces of DNA, but as of now they're incapable of hosting large regions of the human genome, which may include complex mixtures of protein-coding sequences and regulatory DNA.

Both plasmids and viruses, while extremely powerful tools in research and gene therapy, also suffer from the same size limitations as transposons, and they have issues transferring multiple copies of the same gene. Additionally, all three methods result in DNA insertion at random places in the host genome, with potentially unwanted results. That's why the possibility of efficiently and stably transferring enough genetic material into humans to allow for traits even remotely similar to those imparted by BioShock's plasmids is currently a simple fantasy.

But the possibility may not be a fantasy forever. The next logical step in addressing these issues would be the creation of synthetic DNA constructs that can be introduced into human cells. These constructs could contain masses of DNA and exist independently from the rest of the genome—a human artificial chromosome (HAC).

Efforts to chemically synthesize entire plasmids and chromosomes are nothing new. But recent advancements in the rapidly expanding field of “synthetic biology” have yielded some truly remarkable results.

In 2006, the J. Craig Venter Institute—founded by world-renowned geneticist Craig Venter—patented what his team named the minimal bacterial genome. This electronically stored genome contained what Venter's team concluded was the absolute minimum genetic code required for a bacterium to survive and propagate. Its purpose? To eventually act as the metaphorical backbone to the first partially synthetic bacterial species, Mycoplasma laboratorium.

The Venter Institute reached another milestone in 2010 when Science published a paper describing the first transplant of a completely synthetic genome into a “blank” bacteria. The chemically synthesized genome originated from an electronically stored copy of the Mycoplasma mycoides genome sequence. The whole genome—which in bacteria consists of a single, circular chromosome—was then inserted into an inactive and DNA-less Mycoplasma capricolum, a close relative to M. mycoides. The resulting organism was completely viable and successfully replicated into billions of genetically identical offspring.

A collaboration between American, British, Chinese, and Indian laboratories is attempting to take this technology one step further. The Synthetic Yeast 2.0 project, based at the Johns Hopkins School of Medicine, aims to chemically synthesize a minimalistic genome for insertion into a “blank” household yeast, Saccharomyces cerevisiae.

It's important to note that yeast cells are fungal, not bacterial. They are much larger and have a complex cellular structure similar to humans and contain numerous distinct chromosomes—16 to be precise.

The success of Synthetic Yeast 2.0 would open the door to other customized yeast genomes. Used at an industrial scale, these made-to-order yeasts could produce vaccines, biofuels, and other biochemicals that cannot be synthesized by bacteria. Additionally, this yeast could contain particular sections of the human genome for a steady supply of naturally produced human proteins.

The potential applications of Synthetic Yeast 2.0 are so great that the British government has recently granted £1 million (more than $1.5 million) to Imperial College London to synthesize yeast chromosome number 11. And that's separate from the approximately £60 million (more than $98 million) devoted to several new synthetic biology research centers and a new innovation center to help unite research and industry commercialization.

Gene alterations

How do these scientific advancements in yeast relate to human genetic augmentation? Well, it stands to reason that if artificial chromosomes can be introduced into a yeast cell, the same process could theoretically be performed with human cells.

In July of this year, The Independent reported on unpublished work by the US National Cancer Institute (NCI) claiming that a research team successfully synthesized, from scratch, the first human artificial chromosome (HAC). Not only that, but the HAC had been inserted into a strain of genetically engineered lab mice, where it remained stable without disturbing the function of the murine chromosomes.

Needless to say, the implications of the NCI's work will be momentous. Sections of the US government have already turned their gaze to the future of HACs, with DARPA issuing a public solicitation that will award a substantial grant to any laboratory willing to research new and improved HAC methodologies.

But NCI researcher Dr. Natalay Kouprina has already envisioned the next step for HAC development—a new generation of powerful, tailor-made therapies to replace genes that have suffered damage and carry mutations that lead to disease.

“The purpose of developing the human artificial chromosome project is to create a shuttle vector for gene delivery into human cells to study gene function in human cells,” Kouprina told The Independent. “The idea is to take skin cells from a patient, turn them into stem cells, and insert HACs into these stem cells with healthy copies of the disease gene. These cells, with the extra chromosome, can then be inserted back into the patient to treat the illness.”

Major strides in HAC development have also been made by the Institute of Regenerative Medicine and Biofunction of Tottori University, Japan. The institute has published a steady stream of findings since the start of 2013 regarding its human artificial “mini-chromosomes”—constructs created by cutting away full-size human chromosomes or by joining small chunks together. It’s also working on efficient systems with which these can be transferred to mice.

For example, one successful experiment involved fully grown mice containing mini-HACs with a multi-gene region of the human genome. The region contains members of the CYP3A family of human proteins, which metabolize roughly half of all modern drugs. Mice containing the human version of CYP3A would offer an exceptionally useful model for testing new human drugs.

A similar experiment was performed with type A haemophiliac murine stem cells. The culture of cells was introduced to mini-HACs containing genes FVIII and PF4—human genes responsible for blood coagulation that are faulty in type A haemophiliacs. The experiment was successful, resulting in murine stem cells where haemophilia was partially counterbalanced by the expressed FVIII and PF4 genes.

All told, the story of molecular genetics, from its founding in the 1950s to present-day research into gene therapies and HACs, is a tale that’s even more fascinating than any of the genetic possibilities offered by BioShock. Genetic technologies are not only becoming more advanced as the years go by, they're also getting an awful lot cheaper.

It's unlikely that BioShock fans will be getting their hands on Incinerate or Electro Bolt any time soon, but groundbreaking HAC and stem cell research, combined with the ever-advancing synthetic genome technologies typified by the J. Craig Venter Institute and the Synthetic Yeast 2.0 project, may mark the beginning of a new era of human genetic augmentation.