Viruses and bacteria don鈥檛 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鈥檛 get sick鈥攂ut 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 , biochemists George Smith and Sir Gregory Winter, found ways to use nature鈥檚 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 鈥榩hage display鈥�.
What鈥檚 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:
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鈥檝e 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 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鈥檚 genetic code responsible for building its protective outer coating, he 鈥榯ricked鈥� the phage into incorporating a bit of that other protein into the coat-constructing process. The phage then 鈥榙isplayed鈥� 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:
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 鈥榮ticking鈥� 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 鈥榮tick鈥� get washed away. It鈥檚 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鈥檚 team 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鈥攕o why not use antibodies as the basis of new pharmaceuticals?
鈥� what if clever use of viruses and bacteria could be used to make new medicines?
You can鈥檛 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 鈥榩hage display鈥� 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鈥攅ach 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 鈥榯arget鈥� as a kind of molecular fishing hook, scooping out the phages with the 鈥榮tickiest鈥� 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:
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鈥檚 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鈥檚 disease. We鈥檝e figured out how to use the principles of evolution to engineer new treatments for disease鈥攚ho knows what we鈥檒l discover next?
This article was written by Emma Berthold , Content Producer, 精东视频 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
