Jan 17, 2019 · 35m · a16z
a16z Podcast | All About Synthetic Biology
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gold bands on the timeline = statements, start to end. Hover to read, click to jump. CC turns on captions
In this episode of the a16z Podcast, synthetic biology pioneer Jim Collins and a16z General Partner Vijay Pandey explore the history, engineering principles, commercial models, and future potential of biological design. They trace the field's progression from early genetic toggle switches to living therapeutics, machine learning integration, and global environmental solutions.
How this conversation actually went
Every chapter scored 0–10 on four independent dynamics. Hover any point for the reasoning behind the score. How this is scored →
The host as informed peer 3.3 Guest teaching 3.6 Guest disagreement 0.9 The host pushing back 0.7
speaking balance: gold is the host, purple is the guest (3 minute bins)
Sharpest disagreement ▶ 10:10 Collins criticizes biological control standards
Collins forcefully dismisses conventional biology controls, asserting that claiming a knockout gene alone explains a phenotype is absurd from a systems perspective.
Hardest push from the host ▶ 10:49 Hanne challenges the academic tribalism framingHanne directly challenges Collins's assertion that friction between fields is merely academic tribalism, arguing instead that it stems from a deeper discomfort with alternative modes of knowledge.
Biggest teaching moment ▶ 19:13 Engineers seeing directed evolution as cheatingCollins educates the hosts on a surprising cultural rift, explaining that traditional bioengineers reject Nobel Prize-winning directed evolution because they view unguided optimization as cheating.
The host holds their own ▶ 18:50 Vijay articulates the core philosophy of science vs engineeringVijay demonstrates deep subject expertise by framing the exact epistemological difference between scientists and engineers in terms of their contrasting ends and means.
the scores for every segment, with the reasoning behind each
| Chapter | Topic | The host as informed peer | Guest teaching | Guest disagreement | The host pushing back | Why |
|---|---|---|---|---|---|---|
| Origins of Synthetic Biology and Reverse Engineering Networks | 2 | 5 | 1 | 0 | The hosts ask foundational questions about the origin story of synthetic biology and reverse engineering biological networks. Guest Jim Collins explains how biomedical engineers initially lacked network models, using a house circuit breaker analogy to explain reverse engineering. | |
| Creating the First Genetic Toggle Switch and Repressilator | 2 | 5 | 1 | 1 | Collins recounts the creation of the genetic toggle switch and repressilator, noting how mainstream biologists dismissed the idea as impossible. The hosts inquire why funding and acceptance were difficult, with Hanne noting that biologist concerns sounded reasonable. | |
| Cultural Differences Between Biologists and Engineers | 4 | 3 | 2 | 2 | Co-host Vijay Pande introduces analogies comparing electrical engineers and physicists to explain the culture clash between biologists and engineers. Hanne pushes back slightly on Collins's 'tribalism' framing, arguing it stems from deeper epistemological differences in modes of knowledge. | |
| Engineered Bacteria as Living Diagnostics and Therapeutics | 2 | 4 | 0 | 0 | Collins details how E. coli was chosen as a workhorse organism and how engineered bacteria evolved from environmental biosensors to living therapeutics for diseases like cholera. The hosts prompt the overview with standard interview questions. | |
| Engineering Design Principles and Parallel Iterative Testing | 5 | 3 | 1 | 1 | The segment explores engineering approaches versus design principles, with Collins highlighting parallel iterative testing. Vijay provides a key insight distinguishing scientists and engineers based on how they treat understanding and function as means versus ends. | |
| Combining Directed Evolution, Machine Learning, and Synthetic Biology | 5 | 3 | 1 | 1 | Collins reveals that bioengineers often view directed evolution as 'cheating' compared to rational design, while Vijay highlights machine learning as a potential third paradigm and references evolutionary approaches in hardware design. | |
| The Synthetic Biology Hype Cycle and Bioenergy Lessons | 3 | 4 | 1 | 0 | Vijay frames the discussion around the synthetic biology hype cycle, leading Collins to recount the mid-2000s bioenergy bust where producing one dollar of gas cost eight dollars. Collins explains how the field subsequently regrounded itself in biomedicine and CRISPR. | |
| Commercial Business Models: Platforms versus Products | 5 | 2 | 1 | 1 | Vijay and Collins engage in an industry analysis comparing platform and product business models in biotech. Vijay draws on venture experience to outline investor dynamics and the single-asset trap for platform companies. | |
| Hands-On Bio Education with BioBits and Cell-Free Technology | 2 | 3 | 0 | 0 | The conversation turns to STEM education, where Collins describes developing BioBits kits using freeze-dried cell-free extracts so students can run synthetic biology experiments safely at home. |
Statements from this episode (21)
Collins: Biomedical engineers played a minor role in early genome efforts
“And what's interesting is the biomedical engineers did not play a major role in the genome effort.”
Collins: Only seven public microarray datasets existed in the late 1990s
“And when I got pulled in, there were only seven publicly available data sets. So the idea you could reverse engineer large scale network was ludicrous.”
Collins: Leading molecular biologists insisted synthetic genetic toggle switches were impossible
“We had talked to about six or seven very serious molecular biologists who told us this couldn't happen, this couldn't work. They said for it to work, you're going to have to have a very tight off state, two very tight off states. That's going to be impossible.…”
Jim Collins: Synthetic biology team built functional genetic toggle switch in nine months
“Nonetheless, in nine months, he had a functioning bistable toggle switch.”
Collins: Single-gene knockout attribution is absurd from a systems standpoint
“I maintain that in almost every biology experiment paper I've read, they've never had the controls that I'd like to see. Which is the idea that you can knock out a gene and that what's lacking and now can be attributed to the gene is absurd from a system stand…”
Jim Collins: Engineering models have predictive value without mechanism knowledge
“An engineer can do remarkably well in many instances with little, if any, understanding of mechanism. And that we'll get after a black box. You can represent a model that gives you some sense of relation between the input and output of, say, going back to our …”
Collins: 30% to 40% of E. coli genes remain functionally unannotated
“There still is a high percentage of the genes that are not functionally annotated in E. Coli, 30 to 40%.”
Collins: Synthetic biology currently lacks established quantitative design principles
“A major challenge in engineering biology, and more broadly, specifically synthetic biology, is that we don't really know the design principles.”
Collins: Serial biological testing takes 20x longer than parallel engineering
“The young biologists in my lab will instead pick one design, one embodiment of that design, and they're going to drill down in great detail Over, instead of two weeks, over six weeks. Realize that it didn't work, and then they're going to go and create the nex…”
Collins: Engineers prioritize functional biological results over understanding mechanisms
“The scientist is curious, wants to understand, is looking for discovery. The engineer wants to get it to work, and doesn't necessarily care do they understand how it works, but that it works.”
Jim Collins: Engineers in his lab resist using directed evolution
“I've been in the SynBio world now for about two decades, and I have yet to get significant buy-in from the engineers in my lab for doing directed evolution.”
Collins: Combining synthetic biology, directed evolution, and ML is the future
“I think the marriage of direct evolution with synthetic biology really is also the future, coupled to machine learning.”
Pandey: Synthetic biology has passed peak hype into practical deployment
“My read on is it's gone past peak hype and is sort of in the, now getting into production, getting to useful.”
Collins: Synthetic biology has been hampered by excessive hype from the start
“Synthetic biology has been hampered by basically too much hype from its very beginning.”
Collins: Early bioenergy synbio firms spent $8 to produce $1 of gas
“So many of these early companies got to be pretty good at producing one dollar worth of gasoline, but it cost them eight dollars to do it, which was a horrible business model.”
Collins: Platform bio startups target tech VCs; product startups target biotech VCs
“The platform companies in this place are playing to the technology investors. And the product companies are playing more toward the traditional biotech investors.”
Pandey: Promising clinical assets force platform bio companies into single-asset firms
“The other thing that happens is that it's very tempting to, once you've built a platform and you actually have an asset that is, let's say, past phase one or phase two, that becomes worth so much. It's a hard financial decision to take money away from that and…”
Collins: In-house manufacturing significantly increases synthetic bio firm valuations
“Having the ability to manufacture your product in house significantly increases your value.”
Collins: The 21st century will be the century of synthetic biology
“I think in many ways this century is going to be the century of biology, and really to put point on it, I think it's going to be the century of synthetic biology”
Collins: Companies are using synthetic circuits to program pathogen-resistant plants
“You're increasingly seeing companies turn towards synthetic circuits to Alter traits in a programmable fashion of plants and to enable them to be more robust to pathogens.”
Collins: Synthetic bio will drive carbon capture and coral restoration within a decade
“I think climate is really just beginning to excite the community and broadly environmental issues on two counts. One is in what way could we use algae and other organisms to pull more carbon out of the atmosphere? Can we help reverse the trend on using biology…”