editorial Awards for manipulating technologies The 2018 Nobel prizes in chemistry and medicine celebrate tools for engineering biological materials.

t may seem that there is little connecting of pathogens or diseased cells. CTLA-4 the 2018 Nobel Prize in Chemistry, and PD-1 are fundamental components Iawarded to Frances H. Arnold, George of that regulation mechanism. Motivated P. Smith and Sir Gregory P. Winter for by previous evidence suggesting that the the directed evolution and phage display activation of the immune system could of proteins, and the 2018 Nobel Prize in be harnessed to attack tumours, James Physiology or Medicine granted to James Allison looked for a general strategy P. Allison and Tasuku Honjo for cancer to fight cancer by relieving CTLA-4 immunotherapy. Notwithstanding, both inhibition of T-cell activation. He used prizes celebrate engineering technologies monoclonal antibodies to block CTLA-4 to generate enzymes, antibodies and cells and found that this treatment had cured with novel properties to tackle some of Three-dimensional representation of CTLA-4, mice carrying tumours6. Honjo and the world’s current problems. a T-cell surface receptor involved in immune collaborators followed this concept and Nearly 30 years ago, after unsuccessful regulation. Credit: molekuul.be/Alamy Stock Photo showed that targeting PD-1 inhibition also attempts to create new enzymes using resulted in an immune attack of tumours traditional engineering, Frances Arnold in mice7. These studies established a new devised a novel protein engineering tool potential of such approach for the directed type of cancer immunotherapy that uses termed directed evolution of proteins1. evolution of therapeutic antibodies. He antibodies (checkpoint inhibitors) to This approach, inspired in the events that generated a library of phages with billions engineer a response from the immune define natural evolution, might be regarded of antibodies at their surface, selected those system against tumours. Monoclonal as a biochemistry equivalent of selective that recognized particular proteins and antibodies targeting CTLA-4 or PD-1, breeding. It uses random mutagenesis to used random mutations to create a new such as ipilimumab, pembrolizumab and generate a pool of protein mutants that are library, from which he selected antibodies nivolumab, are now approved therapies tested for desired properties or substrates. with increased selectivity and affinity for against metastatic melanoma and bladder The mutant with the higher activity is then their target3. In collaboration with others, cancers. Ongoing clinical trials suggest that selected for additional cycles of random Winter further developed this technology this therapy seems promising against lung mutagenesis and in vitro selection until to produce pharmaceuticals, leading to and prostate cancers. Nonetheless, being the wanted features are attained. In its first the first fully human monoclonal antibody based on the induced overstimulation of demonstration, Arnold evolved a subtilisin (adalimumab) approved by American and the immune system, adverse autoimmune variant, an enzyme that breaks down European drug agencies to treat rheumatoid side effects are common. This is currently proteins, whose activity in a water/organic arthritis in the early 2000s. Its therapeutic being tackled with the development of new solvent mixture was hundreds of times applications have now been extended to checkpoint inhibitors that, by increasing higher than the original one1. Since then, several other autoimmune diseases, such as efficacy and reducing side effects, will this protein-engineering technology has Crohn’s disease and psoriatic arthritis. This hopefully contribute to make this type been widely used, and nowadays directed success sprouted the use of phage-display of cancer immunotherapy more effective evolved enzymes are found in modified technology in drug discovery, and safer. organisms that break down environmental which has produced antibodies to treat The technologies awarded with the pollutants and transform carbon biomass distinct cancers, such as gastric and 2018 Nobel prizes in chemistry and into biofuels. Others are employed as colorectal tumours, as well as vision loss and medicine have significantly contributed greener and more efficient alternatives to anthrax infection. to new biological tools to address some synthetic metal catalysts used in industrial The 2018 Nobel Prize in Physiology of mankind’s present challenges. As new chemistry, in the production of non-toxic or Medicine recognizes an immune cell- biomaterials are made available by these pesticides, cosmetics and detergents, as well modulation technology that uses antibodies engineering approaches, further benefits as drugs to treat diabetes and cancer. targeting the cell surface proteins of T-cells, are expected. ❐ Directed evolution of proteins can also cytotoxic T-lymphocyte-associated protein be done with the phage-display technique 4 (CTLA-4) (pictured) and programmed awarded with the other half of the Nobel cell death protein 1 (PD-1), to relieve the Published online: 12 December 2018 Prize in Chemistry. In 1985, George Smith inhibition of the immune system and elicit https://doi.org/10.1038/s41563-018-0264-5 reported that peptides fused to the gene of an attack on tumours. In independent the coat protein of bacteriophages (viruses studies4,5, James Allison and Tasuku Honjo References that infect bacteria to proliferate) are demonstrated that CTLA-4 and PD-1 are 1. Chen, K. & Arnold, F. H. Proc. Natl Acad. Sci. USA 90, 5618–5622 (1993). expressed at the phage’s surface as part of negative regulators of T-cell activation, 2. Smith, G. P. Science 228, 1315–1317 (1985). its capsule protein2. He later demonstrated each through different inhibition 3. Marks, J. D. et al. J. Mol. Biol. 222, 581–597 (1991). that these phage-displayed peptides can mechanisms. T-cells initiate immune 4. Walunas, T. L. et al. Immunity 1, 405–413 (1994). 5. Freeman, G. J. et al. J. Exp. Med. 192, 1027–1034 (2000). be selectively purified from a mixture of responses and thus their activation is 6. Leach, D. R., Krummel, M. F. & Allison, J. P. Science 271, phages using antibodies in a process known tightly regulated to guarantee that a 1734–1736 (1996). as biopanning. Gregory Winter realized the response is only triggered in the presence 7. Iwai, Y. Proc. Natl Acad. Sci. USA 99, 12293–12297 (2002).

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