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Bacteriophages don’t get enough press. There are more of them on this planet than every other organism, including bacteria, combined. Thats in the region of 10^31.
I think I need to lie down…
🤷♂️ Problem
Antibiotics are overused in both humans and animals. In the US, up to two fifths of antibiotic prescriptions could be inappropriate.
According to the WHO, antibiotic resistance is one of the biggest threats to global health, food security, and development.
Currently it accounts for 700,000 deaths a year. Unless something is done, that number is expected to rise to 10 million by 2050.
💡 Solution
Develop new anti-bacterial treatments using bacteriophages - a type of virus that invades bacterial cells (rather than human cells), turns the bacteria’s resources towards making more viruses, and ultimately stops bacterial infections from spreading.
📖 Terms
Bacteriophage. Known informally as a ‘phage’. It is a virus that infects and replicates within bacteria. They may contain either an RNA or DNA genome that encode for as little as 4 up to hundreds of genes.
📚 History
The history of bacteriophages is beautifully entwined with European history. It’s a story of scientific collaboration, lost research and the impact of war. And as with most great stories, it starts with an Englishman (no bias here)…
1915. English bacteriologist, Frederik Twort, is the first to discover bacteriophages when he identifies a ‘factor’ that seems to kill bacteria. Despite publishing his findings in none other than ‘The Lancet’, his discovery is largely ignored.
1917. French-Candian microbiologist, Felix d’Herelle, independently discovers bacteriophages (yeh right) by identifying a phage that kills the dysentery-causing bacteria ‘shigella’. He’s the first to propose phages as a possible therapy.
1919. d’Herelle and a gang of medical interns throw caution to the wind and down a ‘phage cocktail’ to check how safe it is. Happy with the outcome and with no ethics approvals to worry about, they give the cocktail to a 12 year old boy suffering from dysentery. His symptoms resolve after one ‘dose’ and he fully recovers after two days.
1921. Microbiologist George Eliava leaves his native Georgia to work at the Pasteur Institute in Paris. Here he meets d’Herelle and gets excited about the therapeutic application of bacteriophages.
1923. Eliava returns to Tbilisi and founds the ‘Eliava Institute’ to focus on the development of phage therapy.
1924. The phage hype is real. d’Herelle gets an honorary doctorate from the University of Leiden as well as the Leeuwenhoek medal (a prestigious award bestowed once every 10 years). He’s subsequently nominated eight times for the Nobel prize.
1930s. Bacteriophage research flourishes in Russia, Georgia and Poland.
1937. With Georgia a part of the Soviet Union, Eliava falls victim to Stalin’s brutal regime. He is arrested, executed and denounced as an enemy of the people. His crime? Pursuing the same woman as the head of the secret police…
1940s. With the world at war, the Soviets and US pursue their own siloed research into bacteriophage therapy. In America, this is led by pharmaceutical company Eli Lilly. However with the isolation and successful purification of ‘penicillin G’, the West loses interest in phage therapy and focuses mainly on antibiotics. Isolated from Western advances, Russian scientists double down on phage therapy, developing successful therapies that were used throughout World War II.
1950s/60s/70s. Russian scientists publish research and results into phage therapy, but the scientific barriers erected by the Cold War mean the research isn’t translated and disseminated throughout the world.
1980s. Western scientists ‘rediscover’ phage therapy, partly influenced by the growing threat of antibiotic resistance.
2009. In the US, phase I trial results are published using bacteriophages in patients with chronic leg ulcers.
2014. Belgium researchers trial phages in burn victims with infected wounds.
2016. Doctors at UC San Diego miss out on coining the phrase ‘pond to bedside’ when they use a bacteriophage isolated from a local pond to treat a life threatening chest infection in an 80 year old male.
💼 Use cases
Phages have uses beyond just treating infections. Here’s a few examples:
Food industry. In the US, several types of phage are used to treat food products including poultry, meat and cheese.
Diagnostics. Phages can be used to detect the presence of certain bacteria in order to help confirm a particular diagnosis. One example is using phages to detect the bacteria Staphylococcus Aureus in blood samples.
Infection control. Phages can be applied to hospital surfaces including tables, curtains and even surgical sutures to help reduce the spread of infection.
Bioweapon defence. Phages have been proposed as a possible defence against anthrax and botulinum toxin.
👥 Players
There’s no shortage or biotech companies specialising in phage therapies. Here’s just a handful…
Adaptive Phage Therapeutics. Founded by a father and son team, APT is a clinical-stage biotech company developing treatment for multi-drug resistant infections.
Armata Pharmaceuticals. Headquartered in California, Armata are another clinical stage biotech focusing on developing targeted phage therapeutics.
BiomX. Wins the award for the best biotech website. BiomX have phage therapies in phase I trials for acne and inflammatory bowel disease, and a pre-clinical trial for cystic fibrosis. They have positive result for oral administration of phage therapies too.
Cellexus. Need more phage in your life? Cellexus offer biotech manufacturing capabilities so you can make more bacteria-destroying viruses. (Cue evil villain laugh).
Eliava BioPreparations. Named for the man (the legend) and the institution which significantly progressed the science of phage therapy, Eliava provide phage preparations for human health and veterinary purposes.
Felix Biotechnology. Felix is the young upstart amongst the established players - graduating from YC Combinator to bring phage therapies to the masses. It’s unclear how they are differentiating themselves from the competition though…
PhagePro. Another biotech, sure. But PhagePro are focussing on deploying phage therapy in deprived communities. Their ‘Prophalytic-VC’ project is trialling the preventative use of bacteriophage to combat epidemic strains of cholera.
Pherecydes Pharma. A French outfit developing phage treatments to treat bacterial infections. Some of their products have been administered under compassionate treatment licenses.
Theraphage. Once you’ve got your tongue round their name, you can check out Theraphage’s approach to using bacteriophages for vaccine development and cancer therapeutics.
Despite the number of biotechs focussing on phage therapies, it’s hard to find a market cap for the industry. This could be a sign of a market yet to mature, a lack of clinical validation or a combination of the above.
🤔 Challenges
Narrow spectrum. Phages are picky. Beyond just targeting a specific bacterial species, they may only be effective against a particular strain within that species.
Cocktails. In order to ensure good coverage of bacterial strains, a cocktail of 6 or more phages might be required. This makes developing phage therapies more complex.
Purity. Phages evolve. Their genetic material can change which means maintaining consistency and potency during the production process is hard.
Clearance. Phages don’t hang around for very long in the blood-stream (just a few minutes). Using them to treat systemic bacterial infections is difficult, particularly when good old antibiotics last for several hours.
Resistance. Bacteria and phages have been battling it out for…millennia. With such narrow spectrum of activity, it can be easy for bacteria to develop resistance. At which point the phage is, well, useless (although see below for a caveat).
Cost. Antibiotics are relatively cheap. From an economic perspective, developing phages and getting people to actually pay for them is easier said than done.
🌅 Opportunities
Rapid testing. Antibiotics are often prescribed empirically because microbiology tests can take days to come back and doctors can rely on antibiotics with a broad spectrum of coverage for the suspected diagnosis. If phages are ever going to be used extensively, rapid testing of the causative organism is required to overcome their inherent narrow spectrum of antimicrobial action.
Leverage resistance. As described in this paper, bacteria will mutate to evade phages. But in doing so, they can inadvertently make themselves either less virulent or more susceptible to antibiotics. Leveraging this ‘resistance arbitrage’ could prove a useful component of combined phage/antimicrobial therapy.
Destroy resistance. Some researchers are using phages laden with ‘CRISPR/Cas’ technology to disrupt genes that confer antibacterial resistance rather than destroy the bacteria itself. In this way, conventional antibiotics can be made to be more effective.
Biofilms. Putting something into the human body, whether it’s a hip prosthetic, a new lense in the eye, or a catheter up the…you know, runs the risk of infection in the form of a ‘biofilm’. A biofilm is multiple tight layers of bacteria with a slimy coating that is hard for antibiotics to attack and penetrate. Phages though…they do a good job of breaking up and dispersing biofilms.
Fewer side-effects. Although phages are picky about which bacteria they’ll actually invade, this can be beneficial in reducing side-effects. Broad spectrum antibiotics are notorious for causing problems like ‘clostridium difficile infection’ where eradication of bacteria in the gut allow the c. difficile bacteria to proliferate and cause problems.
🔮 Predictions
Specific use-cases. Phages are unlikely to be a panacea when it comes to tackling antimicrobial diseases. However for specific infectious caused by specific bugs, they could have an important role to play.
Adjunct treatments. Phages are much more likely to be used in combination with conventional antibiotics. Despite their narrow spectrum, they can still disrupt bacteria in such a way that either makes them less virulent or more vulnerable to antibiotics.
Bioengineering. The phages that will arise as legitimate treatments in the future are unlikely to be ‘cultivated’ from environmental sources, but rather engineered in the lab with a specific goal and target.
🔗 Links
This directory for all things ‘phage’! Labs, companies and people working in the space
This series of blogs by Drew Smith who provides a cynical yet realistic outlook on the clinical value of phage therapy
That’s it for this week - catch ya next time 👋