When we first begin treating bacteria with a new small-molecule antibiotic, it is generally very effective. The antibiotic can quickly kill the problematic bacteria and clear the infection. Unfortunately, using antibiotics also promotes the evolution of antibiotic resistance. That is, when using antibiotics, we select for bacteria that are unaffected or minimally affected by the antibiotic. As a result, these resistant bacteria become more prevalent and the infections they cause become more difficult to treat.
We discussed some ways to prevent antibiotic resistance in a previous blog post. In this post, Dr. Vivek K. Mutalik PhD, Scientist at LBNL and Co-Founder of Felix Biotechnology, discusses how he hopes to use viruses that infect bacteria, phages, to treat antibiotic resistant infections. With the platform they’re developing at Felix, Vivek hopes to find new phages that are able to kill a wide range of bacteria. He also hopes to direct the development of phage resistance toward the evolution of bacteria that are susceptible to other treatments. Read on learn all about the exciting world of phage therapy!
How does antibiotic resistance impact human health?
Antibiotic resistance has a huge impact on human health. Less than a hundred years ago, in our grandparents’ generation, people regularly died of infections we don’t even think about today. A cut or a scratch could be a death sentence. That changed with the discovery and commercialization of small molecule antibiotics, which turned most infections into routine inconveniences. And so we forgot about how dangerous infections could be until the rise of antibiotic resistance. We used antibiotics everywhere, including preventatively for surgical procedures, misprescribing for viral infections, in livestock to improve yields, and for food preservation. Every time we used these antibiotics, we exposed microbes to a selective pressure that favored the survival of antibiotic-resistant microbes. This led to more antibiotic resistant organisms, including pathogens.
It’s also important to note that antibiotic resistance isn’t new. Many antibiotics are derived from natural compounds produced by things like fungi. Thus bacteria have been dealing with antibiotics and evolving resistance for many years. Nonetheless, we began putting more pressure on bacteria to develop resistance to antibiotics when we started using antibiotics to treat infections in the 1940s.
At first resistance wasn’t an issue. We would find a resistant bug and discover a new antibiotic to treat it. But it has become increasingly clear that we’ve run out of ‘low-hanging fruit’ in the small molecule antibiotics space. In addition, small-molecule antibiotics have dose-limiting toxicities in the human body and often have broad activity. They can wipe out the body’s microflora and cause additional negative health effects.
So we’ve gotten what we’ve selected for: overuse of antibiotics has driven the evolution of multidrug resistant pathogens. We’ve run out of ways to treat many of these pathogens.
The articles we see in the news about patients dying from drug-resistant pathogens may seem like one-off cases now, but these patients are unfortunately the first casualties of the next pandemic — a pandemic of antibiotic resistant pathogens that will make routine surgical procedures life-threatening, and will mean many of us will get chronic or long-term infections that damage our quality of life and shorten our lifespan. These infections will be an even bigger threat to our children and the next generation.
What industries, other than healthcare, are directly impacted by antibiotic resistance? How?
Human health often gets the most attention, but antibiotic-resistance has far reaching impacts on everything around us. This includes pets, livestock, crops, and wild animals and plants. And as I mentioned above, we’ve been selecting for antibiotic-resistance genes not just in hospitals, but also through antibiotic use in agriculture and food. These resistant bacteria can then make their way into wastewater and the environment.
Importantly, just because antibiotic resistance arises in one context doesn’t mean it remains isolated to that context. Our water systems, food cycles, animals and healthcare systems are all connected and resistance genes easily spread through them. So we need holistic solutions to address antibiotic resistance. The solutions offered to tackle antibiotic resistance in healthcare can have knock-on effects on every other industry.
In addition, solutions designed to address antibiotic resistance, must be independent of antibiotics discovery pipelines. Such solutions should provide new ways to kill bacteria and to protect our antibiotic arsenal. As a part of Lawrence Berkeley National Laboratory (LBNL), and the Innovative Genomics Institute, my lab is working on developing solutions to antibiotic resistance. We specifically focus on developing phage therapeutics and filling the basic biology/technological knowledge gaps required to bring phage therapies into the main-stream. These include improving phage gene annotation, mapping phage resistance, and engineering phages and phage-like particles to target diverse pathogens.
Phage therapies have been around for a long time. What have been the major hurdles to their deployment and why are you confident about their development and deployment now?
This is the big question, right? After all, phages have been successfully used on a case-by-case basis for a century. So why haven’t we got an approved phage therapy, and why will now be different? There are two major reasons:
- The amazing progress we have made in understanding biology and developing technologies to efficiently/effectively engineer biological systems in the last 20 years.
- We can deploy this knowledge and technology to overcome the greatest single barrier to effective phage therapy: the speed with which bacteria become resistant to phage.
Expanding on the first reason a bit more, our understanding of phage biology has been quite limited until recently. We’ve only just begun characterizing a large number of phages at the molecular level and developing technologies to consistently manufacture biologics like phage. Advances in tools to characterize and understand biology, from high throughput sequencing to gene function annotation and genome synthesis, and their accompanying bioinformatics power, have allowed us to probe biology, including phage biology, better than ever before. This sets the stage for us to effectively discover, optimize, and manufacture phage therapies.
Indeed, on the manufacturing side, the last two decades have seen the rise of biologics as therapies, particularly enzyme and antibody drugs. The development of these therapies has driven a huge increase in understanding how to manufacture biologic therapies. This has resulted in more consistent quality and safer/more effective treatments.
Now the second problem with phage, which I think is the biggest hurdle for phage therapy and is the reason we started Felix Biotechnology: bacteria, including pathogens, readily evolve resistance to phage. In many cases, the selective pressures to develop phage resistance are even stronger than the selective pressures to evolve resistance to small-molecule antibiotics. As a result, resistance appears more quickly!
At this point, you should be asking, “Why should we even bother with phage therapy?” After all, it seems like we’re getting back on the same resistance treadmill: we can find a phage that works for a patient, use it for a short time, then it becomes ineffective as bacteria evolve resistance. Then, we have to go back to phage discovery and do it all over again.
Some groups have tackled this with formulations such as cocktails of phages. These contain multiple phages that target the same bacteria but which use different mechanisms of infection – different receptors for instance. However, based on some preliminary work we’ve seen in pathogen evolution, there are mutations that confer pan-phage resistance. These mutations can thus render phage cocktails ineffective.
With our current healthcare system, it’s incredibly challenging to help patients OR be commercially successful given how quickly phage resistance arises: you’re either not going to make enough to cover the cost of developing the therapy, or you’re going to have to charge a lot to constantly keep feeding that discovery and development pipeline. Neither is a good outcome.
So we took a step back and asked ourselves whether there was a better strategy than fighting evolution because it is a natural process that will inevitably happen. We hit on the idea of not just using phages to kill pathogens, but also using phages that infect pathogens via the traits that actually make them problematic — the traits that cause virulence and antibiotic resistance. When such a pathogen is targeted by a phage, it can evolve resistance. But, in doing so, it will either become less pathogenic, or become sensitive to an antibiotic.
For example, it may lose a protein that pumps antibiotics out of the cytosol but that the phage also uses as a receptor. Alternatively, it might lose a factor that causes inflammation. Many such ‘fitness’ trade-offs are possible. Targeting these traits allows us not just to treat infections, but also to force the pathogen to evolve to a state of less virulence and danger to humans.
To uncover such evolutionary trade-offs at scale, we built the “Functionator” discovery and characterization platform at LBNL (this work just appeared in Mutalik et al 2020). And it turns out we weren’t the only ones thinking of this — Ben Chan and Paul Turner at Yale University were already pursuing this strategy using traditional phage discovery methods. They identified phages that not only killed P. aeruginosa, but that also drive pathogen evolution toward reduced antibiotic resistance and virulence. Even more amazingly, they worked with physicians at Yale such as Dr. Jon Koff, to treat patients on a compassionate use basis – when they had no other treatment options.
Meeting with the Yale team, we realized that our work was incredibly complementary. After some conversations, Rob McBride (Felix’s CEO) optioned the technologies out of LBNL and Yale to start Felix. Now Felix’s team is developing general solutions and phage therapies to help patients suffering from antibiotic resistant infections.
What problems will Felix initially try to solve using Phage?
Felix is starting off by demonstrating that phage can drive trade-offs that make it easier to treat bacterial infections. Our phage will drive bacterial evolution in two main ways:
1) If a targeted pathogen becomes resistant to phage, it will either be less virulent or become sensitive to another form of treatment (e.g. traditional antibiotics)
2) If the targeted pathogen becomes more virulent or resistant again, it will regain its sensitivity to phage
The first therapeutic applications that Felix is going after are treating chronic infections in patients with underlying pulmonary conditions. These patients are the ones at most risk of developing antibiotic-resistant infections. Indeed, they are often chronically taking traditional antibiotics, which besides having toxicity and microbiome effects, ultimately leads to selection for pathogens with antibiotic resistance. These patients often have no other treatment options when traditional antibiotics stop working and their infections then exacerbate their underlying condition. This leads to an awful cycle of respiratory function decline and, ultimately, death.
We think that inhaled phage therapy is the best option to treat these patients. Inhaled phage are delivered directly to the site of infection. With the compassionate use cases spearheaded by Drs. Chan, Koff, and Turner at Yale, we’ve also developed pretty unique expertise in inhaled phage therapy that no one else can match.
Building on our high-throughput phage-host interaction characterization platform, Felix Biotechnology has developed novel ways to engineer phages of diverse size, and fine-tuned host ranges. Specifically, by using a machine-learning algorithm in combination with deeper insights on phage infectivity determinants, the Felix team is identifying specific phage traits that can be engineered and fine-tuned for improved therapeutic potential.
Felix is also interested in a scaled version of host range tuning – both broadening and narrowing the host range a phage can target. I think there’s a lot of focus on just broadening phage host range among phage research labs and companies. This probably feels like a priority because we don’t have rapid diagnostics to immediately identify a pathogen at the patient bedside and determine whether a specific phage will be effective. But with the technological progress we’ve been seeing in both sequencing and functional-based rapid diagnostics in the last 5 years, and even in the last year with combating COVID-19, we should be moving toward a future where rapid diagnostics determine what a patient needs and that’s what they should get — no more, and no less.
What has the process of becoming a co-founder of Felix been like? What have you learned during this process?
This has been a great ride. LBNL is a great place to work. I have been at LBNL for more than 10 years, and my research group continues to work in the area of synthetic biology and functional genomics of bacteria and phages. We also study microbial interactions in diverse contexts. LBNL has an awesome science and entrepreneurial support system and pushes researchers to think about team science and the translational impacts of foundational science.
My role as a cofounder of Felix biotechnology while continuing my research at the Berkeley Lab has been rewarding. My perspective on the different projects I manage, their team structure, deliverables for each project, and their success metrics have improved a lot. The start-up environment makes you realize the urgency of the problem on hand. I have realized that the most crucial component in any initiative is to have a great team that is agile enough to adopt new technologies/information but still keeps focus on solutions that our society needs. Being a scientist is something I really enjoy, and it’s great that I get paid to do something I enjoy.
My perspective and feelings on doing science are well described by Daniel Koshland Jr. from UC Berkeley. He writes in How to get paid for having fun:
“’The one who rides the tiger can never get off’ is an aphorism that expresses society’s dependence on science…. Each advance brings on the need for more science to solve the new problems. Society, which likes to live well, is addicted to the products of science, and fortunately a peculiar set of humans are addicted to solving the problems. I am one of those typical addicts who finds the obstacle course fascinating and the endlessness of the quest utopia”