Humanity’s oldest dream was the domination of nature. In the modern era, this grandly absurd enterprise evolved into the desire to control the driving forces of the universe — the forces within the atom, between atoms, between heavenly bodies and between generations — the process of evolution, the driving force of the living world. The Nobel Prize in Chemistry 2018 has been awarded to three scientists who have accelerated and directed the creative power of evolution by putting “Darwin in a test-tube”.
Frances H Arnold of CalTech had pioneered the directed evolution of enzymes (the natural catalysts that accelerate chemical reactions in all living things), which has become a driver of protein engineering. George P Smith of the University of Missouri and Gregory Winter of the Laboratory of Molecular Biology at Cambridge have been recognised for their work on phage display, a phenomenon that Smith had reported in 1985. An important analytical tool in the laboratory, it is also used to condition T-cells in cancer patients to fight the specific disease they have.
Between them, the two groups of winners of the Nobel Prize for Chemistry have taken humanity’s project to create more useful lifeforms to a new level. The story began in remote prehistory, when early pastoralists and agriculturists used selective breeding to promote traits that they valued — the size of an ear of corn, or the length of the stride of a horse. The principle behind it was explained in 1866 by Gregor Mendel, an Augustinian friar who paid uncommon attention to the peas in his kitchen garden about the time of the sepoy rising in India. He observed the interplay of dominant and recessive characteristics and formulated the laws of Mendelian inheritance.
Seventy years later, Rosalind Franklin and Maurice Wilkins described the structure of DNA, and Watson and Crick’s model of paired nucleotide bases followed.
Armed with the molecular structure of genetic materials, Arnold put the power of Darwinian evolution to work in the lab in 1993. The outcomes were 256 times better than in nature, and this method of directed evolution is now a reliable technique in protein engineering. It is directed in the sense that it has a set goal — the development of an enzyme or other organic molecule which may have pharmacological or diagnostic uses (as in imaging the brain), form a component of biofuels, or digest oil spills. Many of these synthetic molecules are not found in nature, and enzymes created so as to be resistant to denaturing in hostile environments which may be excessively hot, corrosive or subject to high radiation, would be of interest in the future in space applications.
Protein engineering did not begin with directed evolution. But the earlier methods, which basically strung together genetic material into a template from which useful proteins could be made, was unpredictable. The insight that drove Arnold was that the Darwinian process, which works reliably in nature, would be more reliable in the lab, and faster. And since evolution is based on randomness, it must be an element of directed evolution, even if it sounds counter-intuitive.
Evolving new proteins
The work of Smith and Winter focuses on bacteriophages, viruses which infect bacteria, and which can be used to track interactions between proteins. A gene which the phage contains is also introduced into the gene for its protein coat. When it is expressed as a specific protein on the coat, it acts as a displayed signpost of its contents, mapping phenotype to genotype. The interactions of other proteins with these ‘display phages’, which are part of large ‘libraries’ of phages and proteins, can then be tracked. Apart from its use in protein engineering, the method has also been used to determine the antigens of tumours, leading to targeted treatment.
The thread that runs through the techniques whose pioneers have been honoured by the Nobel Committee this year speaks of the greening of chemistry. The processes of the living world, which are far gentler and more sophisticated than industrial tools tend to be, have been harnessed to human ends. The farmers and herders of remote prehistory, the pioneers who began the ambitious project to improve on nature by using its own processes, would be surprised if they knew how far their quest would lead, millennia after their time.
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