Apr 1, 2019 · 40m · a16z
a16z Podcast | What's in the Water at the George Church Lab?
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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, geneticist George Church and Andreessen Horowitz partner Jorge Conde discuss the ethics and technology of CRISPR gene editing, the future of preventive genomics and data privacy, and the unique organizational philosophy driving breakthroughs at the Church Lab.
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 4.5 Guest teaching 3.8 Guest disagreement 1.7 The host pushing back 2.3
speaking balance: gold is the host, purple is the guest (3 minute bins)
Sharpest disagreement ▶ 16:44 Rejection of host's Tinder analogy
Church firmly shuts down Conde's attempt to summarize genetic matchmaking as '23andMe meets Tinder', flatly stating 'No, I am not actually' to insist on full genomic rigor.
Hardest push from the host ▶ 4:55 Host challenges germline editing via guest's own wordsConde holds Church accountable to his past quote describing CRISPR as 'genetic vandalism', questioning whether such an invasive mechanism is acceptable for germline editing.
Biggest teaching moment ▶ 9:19 Church dismantles critics' Mendelian editing thesisChurch educates the host on why critics miss the mark when advocating germline editing for Mendelian diseases, noting that embryo selection via PGD already solves these conditions without gene editing.
The host holds their own ▶ 4:33 Host demonstrates deep knowledge of CCR5 risksConde demonstrates host expertise by bringing up specific medical tradeoffs, pointing out that CCR5 double nulls carry an increased susceptibility to West Nile virus.
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 |
|---|---|---|---|---|---|---|
| Analyzing the Chinese CRISPR Baby Experiment | 5 | 4 | 2 | 2 | Host Conde demonstrates solid domain knowledge by citing CCR5 and double-null genetics. Church reframes the narrative that the experiment was a solo rogue effort by citing author lists and state oversight. | |
| CRISPR Safety, Genetic Vandalism, and Mosaicism | 6 | 4 | 2 | 5 | Host directly challenges Church using Church's own quote describing CRISPR as genetic vandalism to question its germline application. Church clarifies that gene destruction is precisely what is required to disable CCR5. | |
| Evaluating Target Diseases for Germline Editing | 6 | 5 | 3 | 3 | Conde distinguishes between restoring function and gene knockout in germline targets. Church points out that critics' preferred Mendelian targets can be avoided through simple embryo selection without editing. | |
| Ethical Frameworks, Regulation, and Moratoriums | 5 | 4 | 1 | 2 | Host highlights regulatory momentum in cell and gene therapies to guide the discussion. Church explains how historical moratoriums counterintuitively accelerated research infrastructure rather than stopping progress. | |
| Preventive Genomics and Genetic Matchmaking | 4 | 6 | 3 | 2 | Host attempts to summarize genetic matchmaking as 23andMe meets Tinder, which Church directly rejects. Church explains how full genome sequencing combined with privacy-preserving matchmaking avoids severe genetic diseases. | |
| Overcoming Obstacles to Ubiquitous Genome Sequencing | 5 | 3 | 1 | 2 | Host draws on shared startup history to probe why full genome sequencing adoption remains low. Church outlines the three true obstacles: zero-dollar target pricing, encrypted privacy, and public health framing. | |
| Data Privacy, Forensics, and the Personal Genome Project | 6 | 4 | 2 | 5 | Host challenges genomic privacy by pointing out that physical DNA left on a chair makes privacy impossible. Church reframes the risk between surreptitious gathering and self-exposure, detailing counter-hacks like methylation dating. | |
| Personal Health Insights and Scientist-Subject Research Ethics | 3 | 3 | 1 | 1 | Host asks Church what personal insights he uncovered from his own sequenced genome. Church shares personal medical realizations and notes how self-testing exposed painful skin biopsy protocol flaws. | |
| Building the Church Lab Culture and Philosophy | 3 | 2 | 1 | 1 | Host asks about Church Lab culture using vivid metaphors like Willy Wonka's factory. Church explains that recruitment filters for nice people over pure geniuses to maintain a non-competitive culture. | |
| The 'Fail Fast' Paradigm and Multidisciplinary Teams | 2 | 4 | 2 | 1 | Host asks about ideas Church turned down for being too crazy, but Church flips the premise by explaining he pitches the crazy ideas. Church details banning the word impossible and building multidisciplinary teams. | |
| Future Frontiers in Spatial Omics and Multiplex Editing | 4 | 3 | 1 | 1 | Host frames the shift from reading and writing DNA to future frontiers. Church details 3D spatial omics and achieving 10,000 multiplex edits in a single cell. |
Statements from this episode (25)
Church: Chinese government likely knew about CRISPR baby experiment
“I wouldn't characterize it as a solo effort. I've seen the author list. It's quite long, and I also find it unlikely that a government as technically astute and as engaged in observation would be unaware of such an important thing.”
Church: CRISPR is gene damaging rather than precision editing
“So what CRISPR does well, it's often described as editing. It really is damaging, is what it is. It's not really that good at precision editing.”
Church: Double-null CCR5 mutations increase susceptibility to West Nile virus
“That is correct. So there's a risk for almost every preventative and therapy, and this is the risk in this case, in most populations that's considered a smaller medical risk.”
Church: 20% CRISPR T-cell edit efficiency is sufficient in adult HIV trials
“So first of all, in the approved clinical trials on adults that have HIV AIDS, there is a lot of mosaicism. It's considered part of the clinical trial, and maybe as little as 20% are properly edited, meaning double nulls. That's enough though, because all the …”
Church: Off-target edits appear low in first two CRISPR babies
“So the amount of off-target and mosaicism so far for these two babies seems to be low, but time will tell.”
Church: Embryo selection avoids Mendelian diseases without CRISPR editing
“Ignoring the fact that if you're in an IVF, PGD clinic anyway. To do your CRISPR editing of your Mendelian disease, you could just do selection for most of these things.”
Church: Targeting HIV via CRISPR is more justifiable than Mendelian diseases
“Yeah, I think that we want an example of a disease that is very common, and most of the gene therapies are rare, whether they're editing or not, and we want something that's very serious, and certainly HIV falls in that category, So it struck me as a plausibly…”
Church: Gene editing moratoriums will accelerate research rather than halt it
“Well, there probably will be something that looks like a pause, but it will probably be an acceleration.”
Church: Regulatory agencies smooth technological progress out rather than slowing it
“They are not agents of slowing things down. They're actually agents of smoothing things out.”
Church: Regulators favor breakthrough therapeutic platforms over incremental updates
“To some extent, I think they like new technologies more than they like the old ones. The old ones tend to fail because they're so incremental that they're no longer compared to the placebo, they're compared to whatever they're in increment over, whatever thera…”
Church: NIH and NCI allocate only 1-5% of budgets to prevention
“If you look at the pie charts for a number of government agencies, including the NCI, NIH in general, is preventative is sort of in the one to five percent of the pie chart, but its payback is enormous.”
Church: Genetic testing less than whole genome sequencing gives false assurance
“Which is not, there are a very small number of companies that provide whole genome sequencing because everything else, anything less than whole genome sequencing is not medically powerful enough. Anything less than that misses, gives you false assurance.”
Church: Dor Yeshorim has eliminated Tay-Sachs via genetic matchmaking
“And this actually works. So, Dorya Shurim has eliminated significant meningitis disease like Tay-Sachs by practicing a version of this that probably isn't perfectly generalizable, but there are versions of this that could keep a great deal of privacy.”
Church: Genome sequencing must cost zero dollars for mass adoption
“The cost should probably be zero dollars.”
Church: Only 1% to 4% face severe Mendelian genetic risks
“It's this strange thing where one to four percent of the population will have a very big impact on their life. And the bottom line for their care providers, millions of dollars, huge impact on the whole family, if you're one of the unlucky four percent.”
Church: Strong encryption lets individuals refuse genomic subpoenas
“And if it's encrypted so that even you can't hack it, then you can just say, sorry, it's out of my hands. I don't have my genome. If you want my genome, you're going to have to steal it from me. Right? And I think that's where we are today, finally.”
Church: Most medical data sharing for research is an inaccessible silo
“What a lot of people call sharing, even to this day, you know, 13 years later, they call sharing medical data for research is really a silo that's hard to get into. Unfortunately, it's not impossible to get into. It's not really encrypted the way you would wan…”
Church: Lead researchers should sometimes serve as test subjects in studies
“Sometimes it's important for the top researcher to also be a guinea pig in the study.”
Church: The Church Lab prioritizes niceness over genius when recruiting researchers
“So then the biggest filter for me, and I tell this in the first interview, the first conversation I have, is we're looking for people that are nice. We're not necessarily looking for geniuses. We got plenty of geniuses. We're looking for people that are nice.”
Church: Labs should avoid competition by collaborating or leaving crowded fields
“You try not to compete with other labs if you can avoid it. Sometimes it's unavoidable, but you can avoid it by inviting them to work with them. Leaving alone fields where there's plenty of momentum and a lack of interest in collaboration.”
Church: Genetic recoding can render any organism resistant to all viruses
“Biocontainment using recoding is a way that we can make any organism resistant to all viruses and horizontal transfer. Most of these things now work.”
Church: Multidisciplinary teams require hiring people who are already multidisciplinary
“I mainly recruit people who are multilingual, multidisciplinary, because I found it's hard to build a multidisciplinary team From disciplinarians. You have to have a lot of people who already have done two things, and even if you get two people who have done t…”
Church: Lab developed 3D super-resolution mapping for DNA, RNA, and proteins
“We now have tools for doing DNA, RNA, and protein in three-D at super-resolution, finally.”
Church: Lab achieved 10,000 gene edits in a single cell
“So we set the record of 62 edits in the pigs, and we now have edits, so we have 10,000 edits in a single cell.”
Church: Mammoth project aims for ecological hybrids, not true de-extinction
“But for the mammoth, there are lots of reasons. Both for the environment and for enriching the diversity of a living endangered species. So this is not about de-extinction. This is about making hybrids, and many of the species are already hybrids of multiple s…”