Synlogic President and CEO Aiofe Brennan

The vision of assembling new systems from molecular components—expressed by the brilliant French geneticists Francois Jacob and Jacques Monod in the early 1960s—set the stage for the dawn of synthetic biology. With recent developments ranging from the production of biological circuits to the creation of bespoke genomes and even lifeforms, the sun has begun to shine in this emerging field of research. Now, researchers are using the transformative potential of synthetic biology to diagnose and treat disease.

Founded in 2014 in Boston, Massachusetts, Synlogic was the first synthetic biology company entirely focused on therapeutics—a new therapeutic modality known as Synthetic Biotic medicines. Synlogic’s proprietary pipeline includes Synthetic Biotics for the treatment of metabolic disorders including phenylketonuria (PKU) and enteric hyperoxaluria (HOX). The company is also building a portfolio of assets suitable for partnering in immunology and oncology.

But convincing investors of the therapeutic potential of Synthetic Biotics is not without its challenges. Two months after launch in 2015, Synlogic’s stock price peaked above $50/share. In mid-May, however, the price was just a tenth of that, closing on May 24 at less than $4/share. But that is a significant increase on lows in December 2020, when the stock sank to just over $2/share.

GEN Edge sat down with president and CEO Aoife Brennan, and chief medical officer Richard Riese, MD, PhD, to discuss how Synlogic’s progress and the challenges they have faced to bring a synthetic biology product to different markets around the world.

GEN Edge: What was the founding mission and vision?

Aoife Brennan: The company was founded about six years ago by James Collins, PhD, and Tim Lu, MD, PhD, of MIT. The original concept was to engineer bacteria to be reporters for health problems. Jim and Tim conceived of this diagnostic platform based on bacteria, where you engineer a circuit into a bacterium, such that a switch flips if it encounters a specific metabolite within the body that might indicate a disease state, and then you can harvest the bacteria and read what it has encountered.

They went to pitch the idea to Atlas Ventures, a well-known venture capital firm in the Boston area. At the time the microbiome was starting to take off. There were a lot of companies coming to pitch Atlas on the impact that bacteria can have on health and disease. But Atlas wasn’t excited about the diagnostic business models [from] the microbiome companies. They really liked the science of synthetic biology and engineering bacteria to perform specific functions, believing that bacteria can profoundly impact well-being and health.

The first couple of years were focused on making sure that we could replicate some of the work that Jim and Tim had done in their labs and scale this so that we could do multiple different effectors. We had to quickly choose the model organism we were going to use, one of the first really important decisions the company made. We eventually settled on a bacterium called E. coli Nissle, because it had been approved as a probiotic in Europe and Canada. Also, since it’s an E. coli, there were existing tools. The number of tools and the number of technologies in the synthetic biology space has exploded over the past five or six years. But six years ago, there were very few picks and shovels.

The company wanted to be able to start engineering bacteria as quickly as possible. We’ve been working on developing what we call the enabling engine of capabilities needed to start moving forward multiple pipeline programs into the clinic.

What we’re still doing is very unique. I often joke that the thing that attracted me to the company was just the uniqueness. I hadn’t heard of a company applying genetic engineering to bacteria therapeutically, but as a CEO, that makes my life more difficult because I can’t point to other companies. When we started to approach regulatory agencies, they didn’t even know where we fit. We’ve had to do a lot of explaining regarding the technology, explaining why we think it could be a really powerful way to impact health and disease, and then creating a path for this new modality. It’s been a lot of fun, and we’re at a really exciting juncture as a company as a result of a lot of grunt work that has gone on over the past four years or so.

GEN Edge: What approach have you taken to get your product to the market?

Brennan:  We’re focused on establishing that our platform can benefit patients because we see the potential for this to be a new class of medicine. Who knew two years ago that mRNAs would have such a huge impact on our lives? No one knew, right?! This new class of medicine, just like all other classes, allows us to do things differently and help people in ways that are not possible to do with other treatment modalities. So, we’re very focused on engineering bacteria as therapeutics, and we’re building our platform capabilities to allow us to do that. Companies get valued based on their products and taking them all the way through.

Our strategy is to bring programs through to commercialization ourselves. We’ve had to choose programs specifically that would have modest, mid- and late-phase development costs, where we see the ability to do the manufacturing to bring these to patients all the way through, certainly in the U.S. We might do something outside of the U.S. because I think that’s just going to be important in validating our platform, that we can maybe do something for patients and validate that patients are embracing this new way to treat their disease. We have to just prove it ourselves and play that out.

We’re also really intrigued by other areas of science. I think we’re seeing other more traditional pharma companies waking up to the potential of synthetic biology across their entire value chain: using synthetic biology to identify new targets, optimize the manufacturing process, and establish new biomarkers of disease. There’s only so much we can do ourselves. Our focus is on metabolic diseases, and we’re excited by the potential, but we’re also open to thinking more broadly in other disease areas. There’s breaking science here every day.

Synlogic chief medical officer Richard Riese, MD, PhD

Richard Riese, MD, PhD: One of the things that attracted me to Synlogic is that we make our drug product for clinical trials. To me that was important. It gives us such good control over when we want to do the clinical trials and how are we going to do it as opposed to waiting for an outside manufacturer to produce a drug product for clinical trials. We can work in lockstep to get high-functioning development plans as part of our nuts to bolts approach to clinical development.

GEN Edge: What are some of the major hurdles Synlogic has encountered?

Brennan: Often what you assume are going to be the biggest hurdles turn out not to be the biggest hurdles, and some things you completely underestimate become your biggest challenges. When I look back at what I anticipated were going to be the big risks for the company, they turned out to not be such a big deal at all.

The first one is from a regulatory perspective. We read the press about GMOs and think that there’s going to be all sorts of regulatory barriers. But both the regulators and patients have been really accepting and open because they see this as a way to apply a high science to something. Probiotics are a big business globally. Many people are taking these things as supplements. But the quality, safety, and efficacy of probiotics are outside the regulatory paradigm.

I think the FDA embraced our technology as a way to bring a lot of science to study these as drug products, do the usual development, demonstrate safety and efficacy, establish the assays to determine quality, and make sure that there weren’t contaminants in our bacteria —all the things that are important to regulators reviewing products. From day one, our interactions with the FDA have been super collaborative. They’ve been fascinated.

We understand the function of what we were putting into bacteria and how we were changing them. We’ve been really careful about understanding the safety of something we were putting in, making sure that we weren’t modifying the bacteria to give them a survival advantage or introducing anything that might increase the risk of antibiotic resistance— which is a really hot topic from a public health perspective and a regulatory perspective.

So, the FDA has been super helpful. Their scientists have been very engaged in the discussions. We were concerned about getting a different reception when going to other regions where there’s a reputation for being a lot more conservative about genetic engineering and agriculture. But the regulatory interactions that we’ve had have been pretty universal.

Similarly, patients get the concept. They like the idea that it’s a designer probiotic. Some of the diseases we are pursuing like PKU affect kids as well as adults. Kids often have the most challenging time with these diseases because that’s when their brains are starting to form and they can have irreversible cognitive damage. Parents have also been embracing, asking what can they do to help us move quicker. Both those stakeholder groups have been great to work with.

From an investor perspective, it’s a little more mixed. Investors like being able to categorize companies into gene therapy companies versus small molecule companies. We defy that. It’s been difficult. We’ve reached the conclusion of putting our platform into a black box, which pains me because it’s such a cool platform. We just speak mainly about the programs and really only open the black box if somebody wants to go in there and understand the platform of the synthetic biology pieces. We’ve been navigating that space over the past year or two.

GEN Edge: How does Synlogic approach working in different regulatory areas around the world?

Riese: Particularly in our PKU program, we’ve reached out to Canada, Germany, Netherlands, and Israel. We’ve gotten really good advice, complementary to the advice we have gotten from the FDA. As we move our projects forward, we’re going to have to weigh each one. We consider where we want to potentially market products and how we can support them. There’s a variety of models that can be used.

Do we do it all? We’re a small company, so we can’t do everything. Do we work with a partnership supporting different parts of the world? We have yet to figure it all out, but we will as we move along. We’re a U.S.-based company, which has a big market, and we’re starting there. We’ll move on starting with Canada, Europe, and even other places around the world.

GEN Edge: What is Synlogic’s charted trajectory?

Brennan: I use the analogy of a bacterial culture. We’re in the lag phase now. What’s really important is to get the right culture media and conditions during the lag phase because, once you start on your exponential growth phase, it’s very difficult to change culture, to change direction, and to get contaminants out of your culture. We have a real opportunity to set ourselves up for success and make sure we’ve got the right culture, scientific foundation, infrastructure, and people. Once people start to see that we’re moving the needle for patients with diseases and impacting important clinical outcomes in patients, people start to take us more seriously.

We’re hoping that we’re approaching the exponential growth phase as a company. That will come on the back of proof-of-concept data from our ongoing clinical trials. Once we showed that we can do it in one indication, it’s less of a hard sell in terms of doing it in other diseases and in other areas as well. It just makes everything so much easier to have that risk off the table.

GEN Edge: What are the major obstacles to Synlogic’s trajectory?

Brennan: We need cash. We just did a round of financing. We were really happy to get that done and get more fuel into the company. You need investors who have that vision and can see the potential in what you’re doing that are willing to think differently and take risks on new technologies. Without that, none of us would be able to do the work that we do. That’s one piece.

We have a lot of programs lined up to go pre-clinically and I think some of the readouts that Richard and his team are working on this year will really help us speed those forward. We’re building the foundation now. Once we show what we and this platform can do, others will start to see it too. It could be an exciting journey.