Viruses and bacteria don’t have the friendliest reputations. As far as we humans are concerned, we do everything we can to avoid coming into contact with certain types so that we don’t get sick—but what if clever use of viruses and bacteria could be used to make new medicines to treat sickness instead?
Two of the winners of the 2018 Nobel Prize for Chemistry , biochemists George Smith and Sir Gregory Winter, found ways to use nature’s evolutionary processes to make new proteins (much like fellow prize winner, Frances Arnold, who used directed evolution to create new enzymes ). Those methods led to the development of new medicinal treatments, all thanks to something called ‘phage display’.
What’s a phage?
All viruses are relatively simple things, consisting of some genetic material wrapped up in a protective protein coating. They multiply and spread themselves around by finding the right kind of living cell to hijack and inject their genetic material into. The host cell then turns into a copying factory, churning out more copies of this genetic material and pumping new virus particles out into the world (usually destroying the host cell in the process).
A diagram of a typical phage. Image adapted from: Adenosine; CC BY SA 3.0
Bacteriophages (also called phages or phage) are a type of virus that infects and grows inside bacteria and archaea . They are incredibly useful across a range of industries and areas of research, especially for drug development and improving human health: they’ve been used to develop new antibiotics, diagnose infections and they are even being developed to kill disease-causing bacteria.
Panning for proteins
In the early 1980s, George Smith found a way to put proteins (or parts of proteins called peptides) on the surface of bacteriophages to rapidly make many copies of these proteins and then select the best of the bunch for specific tasks. By inserting a gene for a protein into the part of a phage’s genetic code responsible for building its protective outer coating, he ‘tricked’ the phage into incorporating a bit of that other protein into the coat-constructing process. The phage then ‘displayed’ this bit of target protein on the outside of its coat, like a little flag.
Phage display is used to display proteins on the phage surface from an introduced gene. Image adapted from: ©Johan Jarnestad/The Royal Swedish Academy of Sciences
With this approach, you can quickly generate massive libraries of different random peptides by incorporating random genes into the bacteriophages: since the phages grow inside bacteria, rapidly-reproducing bacteria mean rapidly-reproducing bacteriophages, too. Some of these randomly-generated peptides might be useful for research or drug development.
So how do you identify the best proteins out of an entire library of possibilities? You see which phages are the best at ‘sticking’ onto a surface coated with a substance that will only stick onto the kind of protein that you want. The phages displaying inferior proteins that do not ‘stick’ get washed away. It’s like panning for gold, separating the valuable stuff from the rest. With each new round of panning, you end up with a library that has more useful proteins in it, making it easier to find the best one for your needs.
Engineering antibodies to make medicines
Gregory Winter’s team took this process a step further to make antibodies that could be used as medicinal treatments. The human immune system already produces hundreds of thousands of different types of antibodies to fight off specific diseases—so why not use antibodies as the basis of new pharmaceuticals?
… what if clever use of viruses and bacteria could be used to make new medicines?
You can’t just use any old antibody to fight off a disease, though. Antibodies are proteins with very specific shapes and you need the right shape to match a specific disease-causing agent. Winter began to use the ‘phage display’ techniques pioneered by Smith to start engineering custom-made antibodies: insert the genetic instructions for building part of the antibody into the genetic sequence of a phage, and those phages will build those antibody components into their outer coatings. By inserting the genetic instructions for the whole range of antibody genes, huge libraries of different antibodies can be made to display on phages—each phage with a different antibody.
The next step was to find the phages with the antibodies that were the best at latching onto a target. That target could be another protein or a bit of DNA that was part of whatever causes a particular human disease. Winter used this ‘target’ as a kind of molecular fishing hook, scooping out the phages with the ‘stickiest’ antibodies and discarding the rest. Repeating this cycle a few times allowed for the development of antibodies that were able to stick strongly to their targets and could form the basis of a drug.
In this image, the protein (in dark grey) on the surface of the phage (in light green) subtly changes shape, with the shapes shown in the third generation being the best match. Image adapted from: ©Johan Jarnestad/The Royal Swedish Academy of Sciences
Thanks to the phage display method, scientists were able to create the first drug that is an entirely human antibody. Adalimumab (sold under the trade name Humira), a treatment for inflammatory and autoimmune diseases such as rheumatoid arthritis and Crohn’s disease, is now the biggest-selling drug in the world and has improved countless lives.
This is just the beginning: scientists are still using the techniques developed by Smith and Winter to find new antibodies that can be used as treatments to target cancer cells, to block transplant rejection, neutralise the toxin that causes anthrax, and treat Alzheimer’s disease. We’ve figured out how to use the principles of evolution to engineer new treatments for disease—who knows what we’ll discover next?
This article was written by Emma Berthold , Content Producer, Australian Academy of Science and has been reviewed by the following experts: Professor Ross Barnard Immediate Past Biotechnology Program Director & Affiliate Professor, Queensland Alliance for Agriculture and Food Innovation, School of Chemistry and Molecular Biosciences, Australian Infectious Disease Research Centre, The University of Queensland; Dr Martina Jones Operations Manager (National Biologics Facility) and Deputy Director (ARC Training Centre for Biopharmaceutical Innovation), Australian Institute for Bioengineering and Nanotechnology, The University of Queensland
