The Power of Evolution

The Nobel Prize in Chemistry 2018 honored discoveries of tools that in the laboratory can mimic and push/advance evolution. Something that naturally takes millions of years only takes a few days in the lab. Using these tools, a multitude of variants of an original protein with new properties, for example an antibody, can be generated. These can then be tested and modified until a molecule with the desired properties is generated. Enzymes produced through this kind of directed evolution are today used in for example manufacturing of pharmaceuticals, and antibodies evolved using so called phage display can combat autoimmune diseases.

Directed evolution of enzymes

Half of the Prize was awarded to Frances H. Arnold, who is a chemical engineer at the California Institute of Technology in Pasadena. Arnold carried out pioneering work in the 1990s on the directed evolution of enzymes: proteins that catalyze chemical reaction. She developed methods for inducing mutations in enzyme-producing bacteria and then screening and selecting the bacteria to speed up and direct enzyme evolution.

“Nowadays, her methods are routinely used in the chemical industry, for example in the manufacturing of chemical substances, such as pharmaceuticals, and in the manufacturing of renewable fuels for a greener transportation sector,” says Claes Gustafsson, Professor of Medical Biochemistry at the University of Gothenburg and Chairman of the Nobel Committee for Chemistry 2018.

“I am very impressed by Arnold’s ability to develop new enzymes that catalyze reactions that are not catalyzed by naturally occurring enzymes, such as carbon-silicon bonds. I many cases, the enzymes that Arnold has developed offer a more effective and environmentally friendly alternative to the current metallic catalyzed reactions.”

Copying nature’s design process 

Following the Nobel announcement, Arnold explained to Adam Smith of Nobel Media that what she actually does is “copies nature’s design process”:

“All this tremendous beauty and complexity of the biological world all comes about through this one simple, beautiful design algorithm, and what I do is use that algorithm to build new biological things. And to me it’s not … it’s obvious, it’s totally obvious that this is the way it should be done.”

She further emphasized in her speech at the Nobel Banquet that it is all too easy to apply the evolution incorrectly: both in practice and in theory.

In her Nobel lecture entitled “Bringing new chemistry to life”, she described how her discovery is a versatile tool to make this planet a better place. She further emphasized in her speech at the Nobel Banquet that it is all too easy to apply the evolution incorrectly: both in practice and in theory. Therefore, we must use the term wisely. 

Simple evolution in a petri dish

Professor Emeritus at the University of Missouri George Smith is someone who has used the term well. Smith shares the other half of the Chemistry Prize with Sir Gregory Winter. In 1985 Smith developed a method where a bacteriophage – that is to say, a virus that infects bacteria – is used to evolve new proteins. He coined his method phage display, which can be used to quickly select new binding proteins.

Gregory Winter, today Researcher Emeritus at MRC Laboratory of Molecular Biology in the U.K., used phage display for directed evolution of antibodies, with the goal to produce new pharmaceuticals. The first pharmaceutical/drug produced with this method was adalimumab (Humira), which was approved by the FDA in 2002. It has become a blockbuster drug used to treat rheumatoid arthritis and inflammatory bowel diseases among other illnesses.

Since then, phage display has become a powerful tool in drug discovery; it has been used to produce antibodies that may help to cure metastatic cancer, counteract toxins, and treat autoimmune diseases. 

This Nobel Prize has opened up entirely new ways of producing biological pharmaceuticals.

“This Nobel Prize has opened up entirely new ways of producing biological pharmaceuticals. The importance for society and patients can hardly be overestimated; the entire industry of antibody-based pharmaceuticals had a turnover of more than $50 billion in 2018,” says Professor Carl Borrebaeck of the Department of Immunotechnology at Lund University and one of the world’s leading researchers in the field of antibody design.

Carl Borrebaeck, professor, Lund University

Only in its infancy

The Nobel Prize in Chemistry has also indicated new possibilities within antibody-based immunotherapy, which now has evolved to the field of immuno-oncology where the aim is to kick-start the body’s own immune defense to eliminate tumors. 

”Although there are pharmaceuticals on the market, this therapy is only in its infancy, which means that over the next few years there will be a revolution on how we look upon cancer therapy,” says Borrebaeck.

“We are probably only at the beginning of this development because many new therapeutic antibodies, produced through phage display or other techniques, are currently in different stages of clinical trials,” adds Gustafsson.

The Laureates have now laid the foundation and have developed techniques that, in one way or the other are used by the majority of biopharma companies that develop biological drugs.

Their contribution today is a pillar for the development of biopharmaceuticals.

Göran Forsberg, CEO of the Swedish company Cantargia, which specializes in antibody-based cancer treatments, agrees: “These technologies have been a part of our toolbox and will continue to be important in the future to further develop and broaden our project portfolio. Their contribution today is a pillar for the development of biopharmaceuticals.”

Nordic strength

Carl Borrebaeck founded the Swedish company Alligator Biosciences in 2001, which is currently developing antibody-based pharmaceuticals for cancer treatment. The corporation has probably been the most successful in this field in all of Nordic Europe. In 2017, Johnson & Johnson licensed the company’s immune-oncology agonistic CD40 antibody for more than USD 700 million. 

The company started a clinical phase I study in December with ATOR-1015: a drug candidate developed for tumor-directed immunotherapy. The phase I study is a first-in-human dose-escalation study of up to 53 patients with advanced solid tumor disease at five different clinics across Sweden and Denmark. The primary aim will be to investigate the safety and tolerability of the drug and to identify the recommended dose for subsequent Phase II studies.