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The research that earned the 2018 Nobel Prize in Chemistry and its implications for the future
By Sean O'Brien
After another full earth rotation around the sun, the Royal Swedish Academy of Sciences announced this year’s Nobel Prize Laureates in Chemistry. On 3rd October 2018, the winners were revealed as Frances H. Arnold, for “directed evolution of enzymes”, and George P. Smith and Sir Gregory P. Winter, for “phage display of antibodies”. This article focuses on the ground-breaking research carried out by these scientists, along with applications and potential for the future.
Proteins are widely regarded as fundamental to biological systems. One of their most important roles is to function as enzymes, which act as catalysts to speed up reactions. To further understand this research, one must first understand how evolution comes into play. Darwin’s theory of natural selection describes evolution as gradual and dependent upon random mutations. Arnold, Smith and Winter have steered this process into a carefully calculated one, in which evolution is directed, thereby eliminating the randomness and lengthy time scale by which it would occur by natural selection. Improving chemical synthesis by optimising natural products is the end goal.
The research led by Frances H. Arnold, which earned half of this year’s Nobel Prize in Chemistry, involved the directed evolution of enzymes to broaden the capacities of chemical synthesis. This process begins with the introduction of random mutations in the DNA sequence encoding the enzyme. This will cause restructuring of the amino acids that make up the enzyme structure. The randomly mutated genes are then inserted into bacteria to produce large quantities of these new, altered enzymes. The final stage involves selecting the most efficient enzymes for catalysing the reaction of interest. These selected enzymes can then be made even more efficient through further rounds of this process. This can bring benefits to a wide range of industries, such as production of biofuels or pharmaceuticals.
The second half of the Nobel Prize was shared between George P. Smith and Sir Gregory P. Winter, for the evolution of antibodies to fight against autoimmune diseases. Antibodies are large protein molecules composed of four peptide chains, which makes them challenging to produce in large quantities within a laboratory environment. George P. Smith developed a method called ‘phage display’ where the DNA encoding a protein of interest is packaged into a phage (a virus that can only infect bacteria) in a way that results in the protein being expressed on the surface of the phage. Therefore, the phages are essentially protein capsules, or shells, holding the DNA code required to produce the final antibodies. To produce large quantities of a desired antibody, the phages are allowed to infect bacteria with their packaged DNA, like a Trojan horse, so that the bacteria will now manufacture the antibody.
Sir Gregory P. Winter took the phage display method further, using it for the directed evolution of antibodies. Antibodies displayed on the surfaces of phages are tested for how well they bind to their specific target antigen (the unique protein to which an antibody binds). Potential antibodies go through three stages of optimisation, and between each stage the genes encoding the antibodies are randomly mutated. After each stage, the antibodies are refined and become increasingly more effective at binding to their target. This higher binding affinity of antibodies means that lower doses can be used when treating patients, which both saves money and reduces the severity of any side effects. The phage display method is now widely used in the pharmaceutical industry to produce drugs capable of combatting autoimmune diseases, such as rheumatoid arthritis.
The research described here illustrates that we, as humans, have taken a process that can take aeons to occur in nature and sped it up for the benefit of our species. Living in a world where there is constant fear over the destiny of humanity, perhaps it is nice to hear that our future is not entirely out of our hands.
From Issue 16