Jan 16, 2019, 8:46 PM ETInterview

a16z Podcast | All About Synthetic Biology

The field emerged in the late 1990s when the biomedical engineering community, traditionally focused on tissue levels, pivoted to the cellular level to assist genome sequencing leaders.
Engineers and physicists were recruited because molecular biology lacked a dominant framework for understanding complex networks, relying instead on single-protein or single-gene fixation.
The initial challenge was "reverse engineering" biological networks to map interconnected proteins and RNA, a concept native to electrical engineering but alien to traditional molecular biology.
Early attempts failed due to a lack of data; only seven publicly available microarray datasets existed, and wet lab capabilities for perturbation were non-existent.
The discipline shifted from analyzing existing networks to "designing by intent," aiming to construct molecular circuits with specific architectures and functions.

Jim Collins' lab spent nine months designing a genetic toggle switch (bistable memory) modeled after electrical flip-flops, where two mutually inhibitory genes toggle between State A and State B.
The team faced significant skepticism; six to seven molecular biologists deemed the project impossible due to the cellular burden of plasmids and the difficulty of achieving tight off-states.
Graduate student Tim Gardner successfully built a functioning bistable switch in nine months, overcoming the "impossible" verdict despite being trained in mechanical engineering.
In January 2000, Collins' toggle switch and a repressilator (ring oscillator) by Michael Elowitz and Stan Leibler were published back-to-back in Nature, marking the launch of synthetic biology.
Collins describes the initial resistance from biologists as an "immune response against engineering," stemming from academic tribalism and a discomfort with engineering's "black box" utility.

A fundamental cultural divide exists between scientists (driven by curiosity and understanding mechanisms) and engineers (driven by utility and making systems work, often regardless of full mechanism understanding).
Engineers utilize highly parallel, trial-and-error approaches to iterate through dozens of designs quickly, whereas biologists traditionally adopt a serial approach, drilling down deeply into one design over weeks or months.
Engineers often reject "directed evolution" (optimizing via random mutation) as "cheating," preferring rational design to retain control over system tweaking.
The future of the field is predicted to be a hybrid of rational design, directed evolution, and machine learning to navigate vast genotype-phenotype spaces.
Machine learning is identified as a critical frontier, capable of bridging the gap between the data generated by directed evolution and the predictive power of design.

The field suffered a "hype bubble" in the mid-2000s focused on bioenergy, which collapsed because academic-scale successes could not be economically scaled to million-liter bioreactors.
Post-2008, the industry grounded itself in biomedicine, leveraging CRISPR technology and the concept of living therapeutics to create value in high-margin markets like perfumes and rare disease treatments.
Companies in the space face a strategic choice between "Platform" models (e.g., Ginkgo Bioworks) that engineer organisms for various partners and "Product" models (e.g., Synlogic) that develop specific therapies for clinical trials.
Successful companies must navigate the temptation to become "single-asset" companies once a specific product succeeds, often at the expense of long-term platform capability development.
Go-to-market strategies often rely on partnerships with large pharma to manage manufacturing and distribution, though companies face the challenge of timing these partnerships to maximize investor value.

Synthetic biology is entering K-12 education through "BioBits," shelf-stable, cell-free DNA kits that allow middle school students to engineer circuits without live bacteria.
These tools aim to instill "design thinking" in youth, preparing them for a future century where solving problems like climate change and food security requires engineering biology.
Emerging environmental applications include using engineered algae to sequester atmospheric carbon and creating synthetic microbiomes to make coral reefs heat-tolerant against bleaching.
The field is moving past the "hype cycle" peak into a phase of production and utility, with a specific focus on programmable living cells for diagnostics and therapeutics.
Experts estimate that while human capability is often overestimated in the short term, the next 10 to 50 years will see transformative, currently unconceptualized advancements in engineered biological systems.