Andrés Cubillos-Ruiz on Making Antibiotics Safer for your Gut

The Humans of the Wyss (HOW) series features members of the Wyss community discussing their work, the influences that shape them as scientists, and their collaborations at the Wyss Institute and beyond. 

Andrés Cubillos-Ruiz has long been fascinated by the power of microbes. Before coming to the Wyss, he studied how ocean microbes maintain the whole ecosystem of the planet through their metabolic actions. Seeing them work on such a large scale, he grew curious about the ones inside our bodies. Now, he is working to protect the microbes in our gut from the harmful effects of antibiotics using engineered live biotherapeutic products. Learn more about Andrés Cubillos-Ruiz and his work in this month’s Humans of the Wyss.

What are you working on?

I’m working on creating engineered live biotherapeutic products (eLBP) for the prevention and treatment of human diseases. We use synthetic biology approaches to give microorganisms novel functions that can be employed to address specific health issues, particularly from within the human gastrointestinal tract.

What real-world problem does this solve?

The main problem we’re trying to address with our eLBP Validation Project is called antibiotic-induced dysbiosis. In our intestines we harbor a collection of bacteria and other microorganisms that are important to our healthy functioning. Together they make up the gut microbiome. The problem is that whenever you take antibiotics, the antibiotics cannot discriminate between good bacteria and bad bacteria. So, they end up killing the good microbes in your digestive tract, disrupting your gut microbiome balance, and selecting for antibiotic resistant variants. In the short term, it leaves you more susceptible to opportunistic infections, and in the long term it can trigger adverse inflammatory or metabolic conditions that can be detrimental to your health.

Our eLBP is a genetically modified bacterial strain that can protect the beneficial microbes in your gut from this collateral damage. The idea is that whenever you have an infection somewhere other than your gut and need to take antibiotics, you would simultaneously take the eLBP. It will degrade the antibiotic when it arrives to the gut so that the beneficial microbes aren’t exposed to its harmful effects. The eLBP works in a way that doesn’t affect the overall concentration of the antibiotic in your blood stream. So, the antibiotic can circulate through the rest of your body and clear the infection while your gut microbes remain intact.

What inspired you to get into this field?

I am a microbiologist and have always been interested in how microbes are important for our wellbeing. At first, I worked on environmental microbiology. I was amazed by how ocean microbes can control global biogeochemical cycles. They maintain the whole ecosystem of the planet through their metabolic actions.

Seeing how we depend on microbes at such a large scale, I became curious about the ones living inside our body. I started to learn about gut microbes, and I became fascinated by the fact that they accomplish so many important functions, they act almost like an organ. This is when I realized that protecting gut microbes from systemic antibiotics is an important unmet need in healthcare. Given my background in microbiology and synthetic biology, I saw this issue as an opportunity where my work could have an impact.

What continues to motivate you?

Every day I see more and more articles published showing the importance of gut microbes. There are fascinating mechanistic studies demonstrating their roles for proper liver function, the immune system, and the development of infants, to name a few. The activity of microbes in your gut has a systemic effect that has both short and long term consequences in your body. Seeing the growing pool of information motivates me to come up with effective solutions to improve patients’ quality of life and address some important diseases centered around the gut microbiome status.

What excites you the most about your work?

The prospect of creating a new kind of medicine that will have a real impact on people’s health is what excites me the most. The effort of creating a novel therapeutic is in itself very exciting. As we move along towards translation, we start facing unprecedented obstacles given the novelty of our therapeutic modality. The constant learning process and the need to think creatively to overcome atypical challenges are features of my work that I find very exciting.

What are some of the challenges that you face?

As with any scientific endeavor, there are technical challenges that you must sort out every step of the way. For those, you can rely on the scientific method and eventually overcome them. This is what we are used to dealing with as scientists.

However, when looking ahead into an eventual implementation of our technology, we face other types of challenges that cannot be addressed through science. For instance, one issue is that our healthcare system focuses on treating patients rather than preventing disease, which is how our technology could have its biggest impact. When used on every patient taking antibiotics, our intervention has the potential to lower the risk of downstream health issues and slow down the emergence of new antibiotic resistance at a population level. In a healthcare system that is economically centered around treating illnesses, there are not too many incentives or resources to develop disease-preventing products. Understanding these challenges led us to recalibrate the use of our technology to address clinical indications where the protection of the gut microbiome is the actual therapeutic target and thus it can be used as a treatment rather than a preventative.

What is unique about doing your work at the Wyss?

The Wyss is a great place – you see many exciting technologies emerge from the labs here and that type of translational research is impressive. The Wyss is unique in its belief that science should not stay in the lab, there should be a path to translation. The end of a project is not a publication, so everyone is thinking ahead to determine what else they need to do to make what starts at the bench a reality. Researchers are encouraged to take their developments further to make true societal impact.

How has that impacted your work?

Being in this environment has affected my mindset. I no longer think that I just need to get results to publish a paper. What I’m doing right now is building up to have an impact in the real world, past the paper, past the grant funding. With every new idea I am always thinking, how can we make this a reality? How does this work fit with the long-term vision and what else is going to influence the translation process?

I no longer think that I just need to get results to publish a paper. What I’m doing right now is building up to have an impact in the real world, past the paper, past the grant funding. With every new idea I am always thinking, how can we make this a reality?

If you are just focused on the paper, you will set up an experiment so it works within the laboratory context, but you might not introduce real-world challenges and variables. The further you anticipate the future, the better your technology will be designed. The very first project I worked on as a postdoc was specifically focused on proof-of-concept in a lab environment but then I wanted to design something that could ultimately be used in humans, so I had to come up with and incorporate new strategies to make that possible. I did that by looking ahead and seeing what challenges I’d face in the coming three to four years.

How do you collaborate with and receive support from other teams across the Institute?

That’s another great thing about the Wyss, there are so many teams who are so supportive of our work. The veterinary team is incredibly capable and efficient. They enabled us to perform in vivo studies and see actual demonstrations of the efficacy and safety of our eLBP.

The Business Development team has educated us about what it takes to translate our technology. From advising us on intellectual property to finding experts to consult about regulatory development challenges, their involvement is so important in having a broader vision of the translational process.

Generally, just being here with a diverse group of scientists means we get input all the time. My PI is Jim Collins, and in our meetings of the Living Cellular Devices Platform we are always getting feedback on our work from people with different areas of expertise. It is great that here at the Wyss there is always a spirit of collaboration within and between groups.

How have your previous work and personal experiences shaped your approach to your work today?

I mentioned that I previously worked with ocean microbes. Studying the ecology and evolution of these microbes and seeing how they operate and accomplish incredible things in the wild helped me in designing our eLBP. I have been able to incorporate my knowledge of evolutionary biology to develop a new framework to make live biotherapeutics safer. One of the most important parts of making an eLBP safe is planning for biocontainment. Usually, researchers use “kill switches,” which are gene circuits that will stop the microbe from doing an unwanted behavior, however, depending on the selective pressure, these circuits might suffer from mutations breaking the kill switch in a small percentage of the population. Our approach incorporates evolutionary safeguards to prevent this from happening. We design our gene circuits so that natural selection works against the engineered traits, keeping them from spreading into natural populations.

My own experiences make me more passionate about this work. My mom had a medical condition that required her to take antibiotics frequently, and because of the recurrent antibiotic use, she developed long-lasting gastro-intestinal afflictions. Also, when my daughter was a newborn, she had a low-grade fever, and we took her to the emergency room. They wanted to give her antibiotics as part of their routine procedures, and I knew how important the gut microbes were for a developing infant. Luckily, in the end, it wasn’t necessary. The experiences of having two people I care so deeply about being prescribed antibiotics while knowing the potential side effects and wishing there was some way to help has been hugely motivating. Now I approach my work with even more dedication.

I don’t think antibiotics are bad. They are lifesaving medications that are very necessary. However, when we have to take them, we can do a better job of defending ourselves against their negative side effects.

One thing I want to make clear is that I don’t think antibiotics are bad. They are lifesaving medications that are very necessary. However, when we have to take them, we can do a better job of defending ourselves against their negative side effects. I think that in a few years we are going to look back in disbelief that we used antibiotics without any sort of protection for so long.

When not at work, and not social distancing, how do you like to spend your time?

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With my family – I live with my wife and my four-year-old daughter. My brother lives in New York and I enjoy visiting him. I’m originally from Colombia, and I travel to see my extended family whenever I can. Unfortunately, I haven’t been able to for a while because of the pandemic. I enjoy biking and hiking, but also just staying at home and spending quality time with my family.

What’s something unique about you that someone wouldn’t know from your resume?

I like to play an instrument that is typical of some Colombian rhythms called a guacharaca. It is a very simple percussion instrument that makes a scratching sound. There’s no formal training for it but you can learn by listening and trying to recreate the sounds you hear. Some are wooden and used for vallenato, a popular type of folk music from Colombia. Others are metal and called güiros. They’re used in cumbia or merengue music.

If you had to choose an entirely different career path, what would it be?

I think I would have liked to be a musician, particularly a pianist playing in a salsa band. I would have loved to perform a piano solo as part of a big band in front of a large crowd.

What does it feel like to be working on cutting-edge technology that has the potential to have a real and significant impact on people’s lives and society?

The fact that we can identify problems that we don’t have answers for, and then use our backgrounds and skills to find a new solution, is exciting.

It’s rewarding to feel like you are innovating to get to the point where your work is going to help people. The fact that we can identify problems that we don’t have answers for, and then use our backgrounds and skills to find a new solution, is exciting. Even at smaller, incremental points in the project, seeing the support from real patients has so much value. We recently published a paper, and the Wyss produced a press release for us. It got good coverage in the media, and we started to get emails from people thanking us for working on this issue. They told us what problems they’ve had after taking antibiotics. Those small gestures keep me motivated to continue doing this research that could eventually help people like them.

• WYSS TECHNOLOGY - Engineered Live Biotherapeutic Product (eLBP) to Protect the Microbiome from Antibiotics