Treating Metabolic Disorders with Synthetic Biology: Interview with Dr. Aoife Brennan
By Neha Suresh, BridgeBio project member
In the inaugural session of the BridgeBio project’s ‘Leading Ladies of SynBio’ series, we hosted Dr. Aoife Brennan. Dr. Brennan is an experienced physician, Scientist and CEO of Synlogic Therapeutics, a leading biotechnology company. The company is primarily focused on developing treatments for metabolic diseases, including inborn errors of metabolism (IEMs) and liver diseases. By utilizing synthetic biotics (probiotics), they aim to address the underlying metabolic dysregulation in these conditions.
Prior to Synlogic, Dr. Brennan spent six years at Biogen where her latest role was Vice President and Head of the Rare Disease Innovation Unit. Her path to these positions was never linear. She emphasized the importance of remaining open to learning and opportunities along the way.
“Careers are a lot more like lattices, where you can move up or sideways. You can start off as a graduate thinking you want to spend your life in a certain discipline and then pursue an opportunity that takes you in a completely different direction.” Dr.Brennan said.
Dr. Brennan initially wanted to be a physician and obtained her degree from Trinity College in Dublin, Ireland. She practiced as a physician for ten years before moving to industry and focusing on drug development. She described her three career paths - Physician, Scientist and Early Stage Entrepreneur. All three have contributed skills and tools she has used in subsequent roles.
“Part of the reason I am here (as CEO of Synlogic) is because I brought the perspective of a physician to the job, thinking about what synthetic biology can do and bridging these two worlds has been an important component of the story of Synlogic,” Dr. Brennan said, “So I love bridge bio as a concept, because I think it encapsulates just how I to think about careers and opportunities.”
Synthetic Biology for Healthcare: Building Synlogic Therapeutics
Similar to the career trajectory of Dr. Brennan, the journey of Synlogic as an early startup to industry was not a linear one. Jim Collins and Tim Liu, the co-founders of the company, first pitched the company as a diagnostic platform to various investors. There were two programs in the beginning: one for the treatment of elevated ammonia in liver disease patients and a Phenylketonuria (PKU) program.
Using Synthetic Biology To Treat Phenylketonuria:
Patients with PKU are unable to metabolize the amino acid phenylalanine (Phe), resulting in its accumulation. Phe cannot be broken down due to the absence of phenylalanine hydroxylase (PAH) enzyme. Elevated levels of Phe can lead to severe neurological complications. Widespread newborn screening has helped mitigate this disease’s effects. Yet PKU is still the most prevalent IEM, and has no cure.
Synlogic created the first orally administered biotherapeutic for treatment in PKU, and has tapped into a $1 Billion market opportunity globally.
Synlogic’s engineered probiotic uses Escherichia coli Nissle, to produce a Phe-metabolizing enzyme called phenylalanine ammonia lyase (PAL). E. coli Nissle was chosen as it is a bacterium often used in the human gut, has a lot of evolutionary tools at its disposal and is easily scalable. Phenylalanine ammonia lyase (PAL) catalyzes the removal of the amino acid, Phe, to the non-toxic product trans-cinnamate (TCA). The PKU program is currently in phase three trials.
“I would say, the one thing that we learned about the PKU program is that it's really important for any project that you're working on to really understand the problem you're trying to solve, “ Dr.Brennan said, ”SynBio is a solution looking for a problem. And you really have to spend a lot of time understanding the problem, the customer, the patient, really spend a lot of time bringing them together.”
Synlogic is now targeting two other rare metabolic diseases following the success of the PKU program - Homocystinuria and hyperoxaluria.
Using Synthetic Biology To Treat Homocystinuria:
In homocystinuria patients, there is a deficiency of an enzyme called cystathionine beta-synthase (CBS), which inhibits the normal breakdown of the amino acid methionine, which is in turn responsible for metabolizing a toxic amino acid, homocysteine. This leads to the accumulation of homocysteine, and its byproducts in the blood and urine lead to cardiovascular and intellectual abnormalities.Synlogic’s new synthetic biotic is engineered to metabolize methionine in the GI tract to prevent its absorption and conversion into homocysteine.
The future of engineered gut probiotics for diseases holds significant promise in the field of medicine, especially in promoting digestive health and boosting the immune system.
“There's a lot we don't know yet about how the microbiome impacts health and disease. We think an engineered bacterium approach is the right way to correct some of those metabolic issues,” Dr. Brennan said, ”The GI tract is where our immune cells are educated and where they learn tolerance versus autoimmunity. So we think that there's a lot of white space to explore there. It's more high risk, though, because often the relationship between the metabolite and the immune disease is less well understood.”
In future sessions, we will amplify the voices of more women executives in SynBio - learn about their journeys, experiences and technology. The continued support, recognition, and equal opportunities for all aspiring female scientists are crucial for the field of synbio to reach its full potential.
References:
Adolfsen, K.J., Callihan, I., Monahan, C.E. et al. Improvement of a synthetic live bacterial therapeutic for phenylketonuria with biosensor-enabled enzyme engineering. Nat Commun 12, 6215 (2021). https://doi.org/10.1038/s41467-021-26524-0
