The Chemistry Nobel
The Royal Swedish Academy of Sciences has decided to award the Nobel Prize in Chemistry 2018 with one half to Frances H. Arnold ”for the directed evolution of enzymes” and the other half jointly to George P. Smith and Sir Gregory P. Winter ”for the phage display of peptides and antibodies”.
The Science
We live on a planet where a powerful force has become established: evolution. Since the first seeds of life appeared around 3.7 billion years ago, almost every crevice on Earth has been filled by organisms adapted to their environment: lichens that can live on bare mountainsides, archaea that thrive in hot springs, scaly reptiles equipped for dry deserts and jellyfish that glow in the dark of the deep oceans.
Life on Earth exists because evolution has solved numerous complex chemical problems. All organisms are able to extract materials and energy from their own environmental niche and use them to build the unique chemical creation that they comprise.
Enter Frances Arnold. Instead of producing plastics and other chemicals using traditional chemistry, which often requires strong solvents, heavy metals and corrosive acids, her idea was to use the chemical tools of life: enzymes. They catalyse the chemical reactions that occur in the Earth’s organisms and, if she learned to design new enzymes, she could fundamentally change chemistry.

Arnold starts to play with evolution
For several years, she had tried to change an enzyme called subtilisin so that rather than catalysing chemical reactions in a water-based solution, it would work in an organic solvent, dimethylformamide (DMF). Now she created random changes – mutations – in the enzyme’s genetic code and then introduced these mutated genes into bacteria that produced thousands of different variants of subtilisin.
After this, the challenge was to find out which of all these variants worked best in the organic solvent. In evolution, we talk about survival of the fittest; in directed evolution this stage is called selection.
In the third generation of subtilisin she found a variant that worked 256 times better in DMF than the original enzyme. This variant of the enzyme had a combination of ten different mutations, the benefits of which no one could have worked out in advance.
With this, Frances Arnold demonstrated the power of allowing chance and directed selection, instead of solely human rationality, to govern the development of new enzymes. This was the first and most decisive step towards the revolution we are now witnessing, which is called directed evolution.
Today, her research group has developed enzymes that transform simple sugars to isobutanol, an energy-rich substance that can be used for the production of both biofuels and greener plastics. One long-term aim is to produce fuels for a more environmentally friendly transport sector. Alternative fuels – produced by Arnold’s proteins – can be used in cars and aeroplanes. In this way, her enzymes are contributing to a greener world.

Smith uses bacteriophages
Bacteriophages are viruses that infect bacteria. Bacteriophages are simple by nature. They consist of a small piece of genetic material that is encapsulated in protective proteins. When they reproduce, they inject their genetic material into bacteria and hijack their metabolism. The bacteria then produce new copies of the phage’s genetic material and the proteins that form the capsule, which form new phages.
George Smith’s idea was that researchers should be able to use the phages’ simple construction to find an unknown gene for a known protein. When new phages were produced, the proteins from the unknown gene would end up on the surface of the phage as part of the capsule protein. This would result in a mixture of phages that carried multitudes of different proteins on their surface. In the next stage – George Smith postulated – researchers would be able to use antibodies to fish phages carrying various known proteins out of this soup. Antibodies are proteins that function like targeted missiles; they can identify and bind to a single protein among tens of thousands of others with extreme precision. If researchers caught something in the phage soup using an antibody that they knew attached to a known protein, as a bycatch they would get the thus-far unknown gene for the protein.
Through this experiment, George Smith laid the foundation of what has come to be known as phage display. Its strength is that the phage functions as a link between a protein and its gene.around 1990, several research groups started to use phage display to develop new biomolecules. One of the people who adopted the technique was Gregory Winter and it is thanks to his research that phage display is now bringing great benefit to mankind.

The world’s first pharmaceutical based on a human antibody
Greg Winter and his colleagues founded a company based on the phage display of antibodies. In the 1990s, it developed a pharmaceutical entirely based on a human antibody: adalimumab. The anti-body neutralises a protein, TNF-alpha, that drives inflammation in many autoimmune diseases. In 2002, the pharmaceutical was approved for the treatment of rheumatoid arthritis and is now also used for treating different types of psoriasis and inflammatory bowel diseases.
The success of adalimumab has spurred significant development in the pharmaceutical industry and phage display has been used to produce cancer antibodies, amongst others. One of these releases the body’s killer cells so they can attack tumour cells. Tumour growth slows down and, in some cases, even patients with metastatic cancer are cured, which is a historic breakthrough in cancer care. Another antibody pharmaceutical that has been approved neutralises the bacterial toxin that causes anthrax, while another slows the autoimmune disease known as lupus; many more antibodies are currently undergoing clinical trials, for example to combat Alzheimer’s disease.
The start of a new era in chemistry
The methods that the 2018 Nobel Laureates in Chemistry have developed are now being internationally developed to promote a greener chemicals industry, produce new materials, manufacture sustainable biofuels, mitigate disease and save lives.