The Bacteria of Theseus?

Bacteria with entirely synthetic genomes, though controversial, have the potential to revolutionize medicine as we know it.

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Two millennia ago, the Roman writer and philosopher Plutarch posed this timeless paradox: if every plank of a sailing ship is replaced throughout its journey, is it still, fundamentally, the same ship? Seventeenth-century thinkers like Thomas Hobbes and John Locke pondered the question’s meaning with theory and logic, thinking up new ideas of natural law, human nature, and governance in attempts to provide an answer. Today, genetic scientists bring the “Theseus paradox” to life in cutting-edge experiments and research. The subject? The genomic data, or DNA, of Escherichia coli, more commonly known as E. coli.

These unlikely philosophers, termed “synthetic biologists,” exploit the many existing building blocks of life to engineer entirely new biological systems. Propelled by technological advances in computing and DNA sequencing, they have reprogrammed bacteria to invade cancer cells, generate biofuels, and coalesce into vibrant microbial art. These intrepid experiments have not only attracted lengthy queues of big-name customers like Goodyear and DuPont, but have also launched nascent biotechnology companies and startups like Moderna and Zymergen into the spotlight. Rolling in government grants and record-setting investor funds, they are on track to complete their most ambitious experiments yet.

Jason Chin and his team at the British Medical Research Council are at the vanguard of these efforts, having recently reported the successful transplant of the largest-ever artificial genome into living E. coli. These “synthetic” bacteria are identical to their natural counterparts, save for slower replication and more elongated shapes. However, the researchers did not simply bundle the same organism in a different wrapping paper and call it new. In fact, every TCG, TCA, and TAG codon in the original DNA was replaced with a “synonym” codon in the replica. Such a copy-and-paste operation should, theoretically, have muddled the instructions and resulted in a dysfunctional product; and yet, the synthetic bacteria thrive. It is hard to say which is more astounding: the modified DNA molecules functioning identically to the original chains, or the (so far) successful viability of the organism itself.

The scientists’ experimental method was to exploit the inherent redundancy of life’s genetic code: across all organisms, 64 DNA codons encode only 20 amino acids. In nature, the assignment of multiple codons for the same amino acid prevents minor DNA mutations from snowballing into the production of misfolded, broken proteins. In most labs, this inborn biological defense mechanism neither helps nor harms experiments. But in the crafty minds of Jason Chin and his fellow scientists, this redundancy represented a prime opportunity to hijack the bacteria and transform them into prolific protein factories.

After substituting codons at more than 18,000 sites across the 4-million-base-pair bacterial genome, Chin was left with three unassigned codons. Though small, the vacancy adds a whole new dimension of freedom to lab-based protein production. E. coli are already able components of drugs that help treat multiple sclerosis, cancer, and rheumatoid arthritis. Pharmaceutical giants like Eli Lilly depend on robust E. coli populations to supply insulin for medicinal use, yet store them in 50,000-liter bioreactors prone to viral infection. The synthetic bacteria may now be recoded to resist viral infection, potentially saving the industry millions of dollars each year.

Despite being almost entirely artificial, the synthesized bacteria undoubtedly still display the fundamental characteristics of life. That they can move, grow, and proliferate is a development that blurs the once-clear boundaries between the organic and the synthetic. Yes, scientists are optimistic that, if given virtually unlimited freedom to rewire their machinery, they can transform synthetic bacteria into drug-producing factories built for medicinal chemistry. But they are also cautious as they contemplate their answer to a slightly modified version of Plutarch’s paradox: if every part of abacterial genome is replaced, is it still, fundamentally, the same bacterium?