We talk a lot about engineering biology. But what does that mean exactly? When engineering cars, apartment buildings, or software, we start with a design in mind and a set of precisely defined parts that are assembled to create the final product. But how do you engineer a living organism, even a simple one like E. coli or yeast?
This was the topic of the conversation between Patrick Westfall and Fiona Mischel in a recent interview for the Built With Biology podcast “How Do We Design Biology? Get Ready to Be Surprised!” The guest of the podcast Patrick Westfall, who is currently a Senior Director of Microbe group at Inscripta working on the Onyx® platform, has spent years engineering and scaling-up microbial strains for production of various molecules. Naturally, the host wanted to know how an experienced strain engineer approaches this problem.
Unlike engineering a mechanical system, when we start the process of engineering a strain, we are not trying to re-invent biology, but rather alter it to move in the direction of the phenotype we want to create. This involves making changes based on what we know (the rational approach), but also trying to find new potential solutions. To do this, strain engineers use methods like random mutagenesis or adaptive laboratory evolution (ALE) to introduce changes into the organism’s DNA and see how that affects its performance on a phenotypic level.
The question is – how do you decide where to introduce those changes? There are so many variables in biology that finding an optimal solution means sorting through a nearly infinite solution set. “What kind of mindset does it take to find the solutions to problems that have infinite answers?” wondered Mischel.
Westfall had to admit that working with biology is humbling. “For all the things that we know or think we understand, there are a lot of things come out of the left field that we don’t understand.” He gave an example from his previous company where after optimizing a strain through laboratory evolution, employees were asked to guess which mutations were causative. The result of this experiment? Scientists were no better at predicting this than random chance.
“Be open to being surprised,” advised the episode’s guest. “If we’re so focused on solving problems rationally, we’re going to miss opportunities. Looking broadly and being open to the possibility that we don’t know everything allows you to really make progress.”
The podcast is full of strain engineering wisdom and fascinating industry stories, and we encourage you to listen to the whole episode here.