Rebooting Life

Homo sapiens has never been satisfied with Mother Nature’s bounty, tinkering for thousands of years with evolution, replacing natural selection with human selection – just think of chihuahuas and rottweilers. Now, quite suddenly, we have acquired a powerful vehicle on nature’s highway and find ourselves in the driving seat without a driver’s licence. Will we do a better job than the blind watchmaker or will hubris, as the Greeks anticipated, finally bring us down? Synthetic biology is often touted as another disruptive technology of the future. Well, the speculation is over because that future is already with us.

Recap: The genetic code in the nucleus of every cell of every living thing is written in just 4 letters, A, C, G and T, named after the four nucleobases adenine (A), cytosine (C), guanine (G) and thymine (T) that are the coding letters in the double helix, the two complementary coils of base pairs holding the genetic blueprint in DNA.

The instructions in a gene are spelled out in 3-letter words (called codons); therefore there are only 4 x 4 x 4 = 64 possible words in the language of life. But of these 64, only 21 are really needed. This is because the protein molecules that cells make from the genetic recipe in their DNA are constructed out of just 20 amino acids and each codon specifies one of them (apart from the 3 that halt the process – see below). It follows that several different codons, on average around 3, must specify the same amino acid. In other words, there is a lot of redundancy in the system. The cell has a mechanism to read off the gene’s codons in the given order and attach the corresponding amino acids, one at a time, to the end of a growing protein chain. When the chain is complete, it curls itself into a complicated 3-D shape, and becomes one of the many proteins – some 20,000 in the case of humans – that provide the organism’s body mass and determine its life force and function.

Delicate forces of attraction and repulsion between the amino acids control the unique way the chain folds, but at this stage of our knowledge this process is too complicated for us to predict the shape and function just from knowing the sequence in its chain of the amino acids, even for relatively short chains like human insulin, which has 51 of them. It is the external surface that plays the crucial role in a protein’s function.

Here is a short summary of ways to modify the genetic code

Patient tweaking: Ever since we (homo sapiens) came down from the trees and subsequently moved from hunter-gathering into agricultural settlements, we have been tinkering with evolution. For instance, we domesticated wild animals to produce milk, meat and horse power; we selected grasses to produce larger seeds and provide cereals that give us ready sources of energy. But as dog-breeders and rose growers well know, waiting for evolution to do our bidding is a slow and unpredictable endeavour. It may take many generations for a suitable mutation to throw up a modified gene to shorten a dog’s tail or enhance a rose’s fragrance.

Cut-and-Paste from nature: The idea is simple: Isolate and copy a known gene (e.g. the one for human insulin) and splice it into the genetic machinery of a benign bacterium (e.g. e-coli) in such a way that the bacterium follows the instructions on the inserted gene in addition to making its own proteins. Harvest the insulin now made by the subverted e-coli protein factory. Making insulin in this way was the first productive achievement in synthetic biology and was carried out by the San Francisco start-up Genentech in 1978.

Redefine the words: The ability to modify a genome by inserting or deleting segments of genetic code, even single bases, has become fast and accurate since the development of the CRISPR gene-editing technology over the past two decades. The 3 ‘stop’ codons TAG, TAA and TGA tell the cell machinery to stop adding amino-acids when the protein chain is complete. They are used with different frequencies and sometimes in pairs, perhaps as a back-up. A large collaborative project to rebuild the yeast genome from scratch is under way. Many changes will be made in the re-engineered ‘improved’ version of the yeast genome. In particular, the TAG codon, which appears in the natural yeast less often than TAA or TGA, can be systematically replaced by one of the other two. This frees up TAG to be redefined and, for instance, to be made to insert any one of the 500 naturally-occurring amino-acids into protein chains instead of the standard 20 currently in use. In due course, by repurposing other superfluous codons, it will be possible to create novel forms of life built entirely from new raw materials.

Extend the alphabet: An even more adventurous idea involves four synthetic nucleotides labelled P, Z, B, S.  Two new base pairs (P, Z) and (B, S) are added to nature’s (A, G) and (C, T) to create so-called hachimoji DNA (from the Japanese word meaning 8 letters). A proof-of-concept experiment has already shown how the idea can work in practice. It could have interesting benefits:

• Denser storage of genomic information. Codons of length two would still provide a dictionary of 64 words
• Immunity to known pathogens. Life forms created with hachimoji DNA would be safe from attacks by existing bacteria and viruses because their subversive mechanisms would no longer recognise their targets and could never evolve to do so.
• Insights into potentially different forms of extra-terrestrial life. With typically 100 billion stars in each of an estimated 2000 billion galaxies in the visible universe, what are the chances?

All aboard for a brave new biological world!