Phage display is used to discover antibody therapies including Humira for rheumatoid arthritis, Portrazza for cancer, and Benlysta for lupus.
The 2018 Chemistry Nobel Prize honored three scientists for evolving, screening, and optimizing proteins: George P. Smith, Curators’ Distinguished Professor Emeritus of Biological Sciences, University of Missouri, and Sir Gregory Winter, Master of Trinity College, University of Cambridge, UK, were awarded half the prize, with half to Frances Arnold, California Institute of Technology.
The theme of the award is directed evolution, exemplified by the phage-display method that Smith developed and Winter extended. To use the method, researchers put a library of DNA sequences into bacteriophages – viruses that infect bacteria. As the phages replicate, they express the sequences as peptide amino acid chains on their surface. Selecting phages with a trait such as binding to an compound yields the DNA that confers that property. Mutagenesis and more selection optimizes the product.
Academia to pharma
Smith says that not patenting phage display was critical to its spread as a research and development tool. “I could talk about it and give samples to anyone in industry or academia,” he says. “I doubt I’d have received a Nobel Prize if I’d been pursuing intellectual property protection instead.”
“I doubt I’d have received a Nobel Prize if I’d been pursuing intellectual property protection instead.”
He understands the reasons for patents but warns they can restrict creativity. “Ideas are not your property,” he says. “They infect you from other people like viruses. They recombine in your body with other ideas and come out and infect other people. That’s how science – and culture – flourish.”
Winter moved phage display beyond small peptides. “We wondered about using this powerful technique to look at folded proteins, in particular to screen our repertoire of antibodies,” he says, “and it proved to be a great technology.”
Phage-display methods are now standard for developing antibody therapy, thanks in part to Winter’s work as a founder of Cambridge Antibody Technology, developer of adalimumab (Humira).
Education and advising
Both Smith and Winter have moved on from the lab. The day of the Nobel Prize news, Smith visited an undergraduate genetics class, reflecting his work before he retired in 2015.
“The last 6 years of my time at university,” he says, “my major focus was an education initiative.” Funded by the US National Science Foundation, the project increased student diversity and use of mathematics in science, which Smith says was an integral part of his own research.
Smith was “a fabulous collaborator and one of most engaged people in the project,” says Rainer Glaser, now Chemistry Department chair at Missouri University of Science and Technology. He worked with Smith on the initiative and says, “He was committed to increasing quantitative methods in science and especially to helping underprivileged students join the program.” Smith developed a microbial evolution lab class that pushes students to do rigorous experiments and quantitative analysis. This type of lab is usually for upper-level classes, Glaser says, “But George has high standards and developed it for first-year students.”
After “a brief period of having to unretire” for Nobel Prize activities, Smith will write papers from the education initiative. He’ll return to community activities and progressive politics that have always been been a priority for him and his wife Margie Sable.
Winter’s current scientific work is advising investment and life science companies. He cofounded Bicycle Therapeutics, which chemically crosslinks phage-displayed peptides to increase their stability and binding. Daniel Barton, Director of Business Development for Biosceptre, a cancer therapy company where Winter is on the Scientific Advisory board, says Winter advances both science and business, with “intellectual rigor and commercial experience.” Biosceptre’s drug target presents a new challenge to the antibody discovery and engineering technology that Winter helped pioneer, and he has great energy and enthusiasm for that type of work, Barton says. “He is a scientist to his core and remains curious and fascinated by the problems of biology.”
“Sometimes you have to just learn drug development on the job and get on with it yourself. In startups, you have to do a lot of that.”
Winter advises entrepreneurs to think about their commercialization goals and identify if industry partnerships, licensing agreements, or a startup is the best way to achieve them.
“Is the goal to get resources for the lab, validation of techniques developed in the lab, or doing public good?” Earning money is also a motivator, he says, “although I tend to think if you get the other things right, that will take care of itself.”
Managing drug development requires different skills than leading a research group, Winter says, so get help from experienced advisors. That said, reflecting on his first startup, he recalls that funds were scarce because using antibody repertoires and phage display to make human antibodies “seemed pretty harebrained.” He adds, “Sometimes you have to just learn drug development on the job and get on with it yourself. In startups, you have to do a lot of that.”
Photo: Jenny Öhman/Nordic Life Science