July 12, 2020

The man who created the first artificial immune system | Science

Sir Gregory Winter, researcher at the Laboratory of Molecular Biology (LMB) of the Medical Research Council (MRC) in Cambridge, United Kingdom, has been awarded the 2018 Nobel Prize in Chemistry for the development of the technology of libraries combinatorias in filamentous bacteriophages that allows to generate completely human therapeutic antibodies in vitro.

Greg shares half the prize with George P. Smith, and the other half is awarded to Frances H. Arnold. This award once again highlights the unique culture and atmosphere of the LMB, where 11 scientists have previously been awarded the highest award by the Swedish Academy, but more importantly, awards one of the most brilliant scientists, innovators and entrepreneurs of his generation, an authentic "fénix de los ingenios" of biomedicine.

The technology by which Winter receives the highest scientific award is universally known as "phage display", for its English-language denomination. The development of this technology was an exciting race, in which other top-level scientific groups participated and in which Greg's group had to overcome many obstacles such as the development in 1989 of the methodology for the isolation of genes of the variable regions of the antibodies by the polymerase chain reaction.

This approach allowed to build collections of genes (libraries or repertoires) of variable regions of antibodies from various sources: blood, spleen, lymph nodes, etc. In October of the same year, Winter's group demonstrated that it was possible to secrete functional antibodies in bacteria, using a recombinant repertoire of variable domains. A year later in 1990, the Cambridge group demonstrated for the first time that it was possible to "present or exhibit" functionally active antibodies on the surface of a filamentous bacteriophage. As a result of this combination, recombinant phages are produced, each of which has a unique antibody in its capsid.

This technology allows the construction of different types of antibody repertoires, currently completely synthetic

This technology allows the construction of different types of antibody repertoires, currently completely synthetic, and has important advantages, such as avoiding the immunization of animals, and the generation of antibodies against any target, including highly toxic substances or compounds that are highly conserved evolutionarily. This technology was used in the development of adalimumab (Humira) by Cambridge Antibody Technology, a spin-out company of the MRC founded by Greg. Adalimumab, directed against Tumor Necrosis Factor, was the first completely human monoclonal antibody approved in 2003 for the treatment of patients with rheumatoid arthritis.

Nowadays, monoclonal antibodies represent a third of the drugs approved by the regulatory agencies, in pathologies such as cancer, rheumatological diseases, inflammatory diseases, rejection of transplants, etc. Dozens of this type of drugs are in different phases of the clinical trial process.

It can be said that the "phage display" technology mimics the functioning of the immune system in a test tube, to generate human antibodies on demand, while also ignoring the controls that the immune system imposes to avoid the generation of auto-reactive antibodies. This technology has two essential components: the generation of gene collections (genotype), and the presentation of functional antibodies (phenotype), which allows to establish a physical association between phenotype and genotype, of relevant practical importance. I dare to suggest that it is possible to glimpse the imprint of those who were his mentors at the beginning of his scientific career in each of the stages of technology "phage display": Fred Sanger, twice awarded with the Nobel Prize in Chemistry, in 1958 and 1980, for their work to determine the sequence of proteins and deoxyribonucleic acid (DNA); and César Milstein, winner of the Nobel Prize in Medicine in 1984, for the development of hybridoma technology to generate monoclonal antibodies in immunized animals.

Although this has been his most remarkable contribution, the contributions of Greg and his team are spectacular, I would like to highlight here the development of humanized monoclonal antibodies by transplanting the hypervariable regions of a mouse antibody, between human framework regions; and the development of new format recombinant bispecific antibodies, such as the diabody, of maximum interest at the present time for the development of immune redirection strategies against cancer.

Winter remedied the functioning of the immune system in a test tube to generate human antibodies on demand

As an entrepreneur, in addition to the aforementioned Cambridge Antibody Technology created in 1989, Greg has been a promoter of other biotechnology companies such as Domantis in 2000 and most recently Bicycle Therapeutics, all of them with remarkable business success and a considerable social impact, creating employment for quality for young researchers. Greg is also a remarkable manager, has been director of the Division of Chemistry of Nucleic Acids and Proteins of the LMB, deputy director of the Protein Engineering Center of the MRC, and since 2012 is Master of Trinity College of Cambridge. Greg has great personal magnetism and was able to maintain harmony and discipline among a group of more than 20 ambitious post-doctoral researchers from all corners of the world. No doubt this contributed to his success, but nothing comparable to his great talent and creativity to explain the reasons for this award.

Luis Álvarez-Vallina is a professor at the University of Aarhus (Denmark), where he directs the Laboratory of Immunotherapy and Cellular Engineering, and is responsible for the Cancer Immunotherapy Unit (UNICA) of the University Hospital 12 Octubre de Madrid. During the years 1996-1998 I work as a postdoctoral researcher in the laboratory of Sir Gregory Winter funded by a Marie Curie contract of the European Union.


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