Aoife Brennan

Of Microbes And Men

Posted May 29th, 2019 by Aoife Brennan, in Corporate Culture, From The Trenches


This blog was written by Aoife Brennan, CEO of Synlogic Therapeutics, as part of the From The Trenches feature of LifeSciVC.

I am the CEO of Synlogic, a synthetic biology company, where the focus of our work is the development of medicines using engineered bacteria.

I love the science of what we do; it is challenging, innovative and has the potential to make a really big impact for patients. I am also challenged by issues related to organizational development; a topic of frequent discussion among CEOs.

Over the past few months, I have started to see parallels between lessons we have learned in the lab and discussions that would occur in the corner office, if I had an office. I will frequently sit in discussions poring over the most recent batch of data with the scientists when an issue that seems unrelated suddenly becomes clearer. I try to keep my observations to myself in the moment but thought I would share some of the lessons I have learned as I toggle between building an organism and building an organization.

Directed Evolution

To make a new strain, we generally initiate an exploratory-phase project based on an understanding of a disease mechanism that is amenable to modulation using a bacterial-based approach.  This may involve consumption of a toxic metabolite, production of a beneficial metabolite, secretion of a therapeutic protein or a combination of effectors.

If the prototype looks promising, and further digging into the biology is supportive, we will initiate a process of optimization. Our prototype strains are developed using intelligent design but we continue to evaluate additional technologies to create better strains with better in vivo potency. We have evaluated bioinformatics-based approaches that allow us to test thousands of genes and constructs in parallel through our collaboration with Ginkgo Bioworks, and have recently initiated a collaboration with enEvolv to use directed evolution.

The enEvolv process starts with the development of intracellular sensors that signal intermediates in the pathway of interest. These sensors can then be used to select strains that perform optimally under the relevant conditions.

This process of optimization of performance through feedback has many lessons for personal and professional growth;

  1. The importance of ability to adapt. Without an ability to adapt, no amount of evolutionary pressure i.e. coaching, is going to help. We try to assess this during the interview by screening for individuals who have made big personal or career changes and thrived.
  2. The importance of a good sensor system. This can be personal insight or feedback from a colleague. The pace of evolution is going to be a lot slower if the feedback is infrequent. We try to make frequent feedback an expectation for everyone in the organization and provide training to managers to help them get more comfortable giving feedback.
  3. The impact will be greater if we focus on a few traits to optimize. Here the ‘stop doing, start doing, continue doing’ framework has been useful. I also provide written summaries of the performance discussion, highlighting the few areas of focus for change.

Culture

If the engineered strain looks promising, we will start to think about moving it into a fermenter where strains are grown usually at 250 ml scale to support further testing in vitro and in vivo.  Here we use a high-throughput bioreactor called ambr250® which allows us to evaluate many conditions in parallel.

Because we eventually need to manufacture strains at large scale for clinical trials we put a lot of effort into optimizing the process in the fermenter. We have found that the culture media we use in the fermenter can have a huge impact on the subsequent performance of the organism in vivo. While we may need to make tweaks as we move to larger scale, it is generally easier to get this nailed down at small scale.

Organizational culture can be conceptualized as the broth we all work and grow in. When faced with difficult organizational decisions, I would love to boot up the ambr250® and run a sequence of scenarios based on a decision tree to evaluate the potential outcomes. While organizational culture can be difficult to control and measure so precisely, we work hard to communicate our values and run an annual engagement survey for all employees to collect feedback. The more I learn, the greater my conviction that organization culture is critical to performance, can have long-lasting impact and requires constant focus and attention.

The Ecosystem

Following completion of preclinical development and the usual regulatory processes, our oral strains are delivered into the human gut where they encounter a diverse ecosystem.

We have made the strategic decision for our initial programs to ‘disable’ the strains so that they do not colonize the intestinal tract and therefore need to be taken daily. A long-term goal of ours is to understand the rules of colonization, potentially supporting less frequent dosing. This could be particularly impactful for developing-world applications, for example.

It turns out that microbes in the gut shape their environment using different niche-constructing traits and there is an active social dynamic playing out in our GI tract daily. Bacterial traits can be classified as mutually beneficial, altruistic, maladaptive or selfish. A single virulent invader can destroy the ecosystem by co-opting resources and thereby causing disease in the host.

It is difficult not to think about social dynamics within companies and to surmise that we maybe have not evolved all that much from the earliest life-forms. Toxic behavior within companies can be very damaging.  Lack of trust leads to dysfunction and has several causes but a sense that someone is ‘out for him/herself’ and not playing for the team is a common one. Identifying and rewarding the ‘good commensal organisms’ within the company has become an important component of our hiring and talent review process.

Ultimately, success for Synlogic will require that we create a pipeline of organisms that benefit patients with disease and an agile and resilient organization that can leverage these strains into commercial products. I am looking forward to continuing the evolutionary journey.

 

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