Sep 24, 2021 · 26m · american-optimist
Discovering Life-Saving Drugs from Fungi! · Joe Lonsdale
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In this episode of American Optimist, host Joe Lonsdale interviews Hexagon Bio founder and CEO Maureen Hillenmeyer about leveraging genomic sequencing, machine learning, and synthetic biology to discover novel life-saving therapeutics from wild fungal genomes.
How this conversation actually went
Every chapter scored 0–10 on four independent dynamics. Hover any point for the reasoning behind the score. Joe holds 38.9% of the talking time here. How this is scored →
Joe as informed peer 5.2 Guest teaching 3.5 Guest disagreement 0.6 Joe pushing back 0.2
speaking balance: gold is Joe, purple is the guest (3 minute bins)
Sharpest disagreement ▶ 22:25 Blunt rejection of host assumption on antibacterial research
Maureen flatly shuts down Joe's premise that Hexagon must be working on antibiotics out of mission-driven goodwill, firmly stating they do not touch it because the commercial market is completely broken.
Hardest push from Joe ▶ 18:29 Pushback on gender dynamics in venture capitalJoe pushes on why more women don't transition from founding to investing, asking if cultural interest is a factor, prompting Maureen to politely push back that biotech venture already has strong female representation.
Biggest teaching moment ▶ 19:21 Taxonomy of anti-infectives versus oncologyMaureen breaks down biological classifications for Joe, clarifying that anti-infectives target viruses, bacteria, and external fungi, whereas cancer is the body's own cellular machinery gone wrong.
Joe holds their own ▶ 2:08 Joe connects natural warfare to CRISPR mechanismsJoe displays sharp domain synthesis by linking Fleming's fungal defense mechanisms directly to how bacteria evolved CRISPR to snip and remember viral threats.
the scores for every segment, with the reasoning behind each
| Chapter | Topic | Joe as informed peer | Guest teaching | Guest disagreement | Joe pushing back | Why |
|---|---|---|---|---|---|---|
| Introducing Maureen Hillenmeyer and Natural Products | 6 | 3 | 0 | 0 | Joe demonstrates solid foundational biology knowledge by drawing explicit parallels between natural fungal chemical warfare and CRISPR bacterial defense mechanisms against viruses. | |
| Unlocking Unsequenced Fungal Genomes | 5 | 4 | 0 | 0 | Joe accurately quotes wild fungal biodiversity figures, and Maureen explains how historical 'grind and find' dirt extraction has given way to high-throughput genomic sequencing. | |
| Hexagon's Toxin-Antitoxin Discovery Platform | 5 | 5 | 1 | 0 | Maureen educates Joe on Hexagon's core discovery mechanism of identifying toxin-antitoxin gene pairs in fungal DNA, correcting his disease scope to anti-infectives and oncology. | |
| Heterologous Expression via Baker's Yeast | 6 | 3 | 0 | 0 | Joe demonstrates knowledge of computational biology needs and Palantir alumni skillsets while asking how yeast fermentation is used to express fungal gene clusters. | |
| Target Prediction and Standardized Regulatory Pathways | 5 | 3 | 0 | 0 | Joe and Maureen discuss standard FDA preclinical pipelines, with Maureen clarifying that Hexagon innovates on discovery rather than altering regulatory or vivarium protocols. | |
| Clinical Development Timelines and Precision Medicine | 6 | 2 | 0 | 0 | Joe details the stark capital disparity between academic grants ($5M) and venture rounds ($50M+), prompting Maureen to explain why venture-backed companies can scale faster. | |
| Incentives and Cultural Differences in Research | 5 | 3 | 2 | 1 | When Joe speculates about cultural factors limiting female investors, Maureen gently counters by clarifying that she actually sees strong and growing representation among biotech VCs. | |
| The Threat of Antifungal and Antibiotic Resistance | 4 | 5 | 1 | 0 | Maureen categorizes the three classes of anti-infectives and clarifies the severe clinical threat of systemic fungal infections in immunocompromised patients compared to superficial cosmetic ailments. | |
| Fixing Broken Incentives for Anti-Infective Drugs | 5 | 5 | 2 | 1 | Joe assumes Hexagon is developing antibiotics due to mission alignment, but Maureen clearly corrects him that market incentives are broken, making antibiotic development commercially unviable without government intervention. | |
| American Optimism in the Biology Era | 5 | 2 | 0 | 0 | Joe and Maureen share mutual optimism about the 'biology decade', emphasizing how modern biology has transformed into an analytical data science discipline requiring programming skills. |
Statements from this episode (18)
Hillenmeyer: About three-quarters of historical antibiotics come from natural sources
“About three-quarters of all antibiotics over history, were found from natural sources.”
Hillenmeyer: Fungi and humans are surprisingly closely related evolutionary relatives
“Compared to bacteria. There's the tree of life. There's bacteria, viruses way over here. Fungi and humans are actually pretty closely related, surprisingly.”
Lonsdale: Fungal defense compounds can likely target most mechanisms in human cells
“And so there's like thousands of types of things inside of fungi, and a lot of those echo the things and types of our cells, and so because they learn to fight each other in different ways, they can probably target most things in our cells as well.”
Hillenmeyer: Fungi share about 6,000 genes with humans
“So humans have about 20,000 genes we know now from the Human Genome Project. Fungi have about 6000 that are the same in humans, are very similar.”
Hillenmeyer: Only 0.1% of estimated fungal species have been sequenced
“So scientists estimate there's about five million species of fungi on the planet, and only 5000 have been sequenced.”
Hillenmeyer: Big pharma paid bonuses to employees for vacation dirt samples
“People at big pharma companies in past decades would be paid little bonuses to bring back dirt from their vacations to do this kind of grind and find search.”
Hillenmeyer: Lipitor originated from fungal compounds
“That's a blockbuster hundred billion dollar cholesterol drug Lipitor originally found in a fungus because cholesterol is essential.”
Hillenmeyer: Fungi mutated their own pathways to survive producing statins
“So this fungus that evolved the statin originally had to protect itself by mutating its own cholesterol, and we can see that in the DNA sequence, so we call it a toxin-antitoxin pair.”
Hillenmeyer: 99.9% of wild fungi cannot be cultured in laboratories
“So most of these fungi won't grow well in laboratories. That's part of why only the .1% has really been worked on. The 99.9% don't really grow well in the lab.”
Hillenmeyer: Roughly 10 fungal genes typically encode a drug compound
“It's usually about 10 genes encodes one drug.”
Hexagon Bio rediscovered statins and existing drugs using its platform
“So we, for example, rediscovered the statins and some of these existing drugs.”
Hillenmeyer: Genomic data scale enables quant-style search focusing
“As we're getting more genomes and more data it's kind of like the quant effect on wall street effect on wall street. We can start to really see which genomes are going to be useful and which ones are not and focus the search.”
Hillenmeyer: Hexagon Bio discovered fungal compounds targeting cardiovascular pathways
“So we've seen we rediscovered the statins themselves, as I mentioned, we've seen other drugs evolving in that same kind of cholesterol pathway. And we also see other totally unrelated chemicals in unrelated pathways that could also have an effect on cardiovasc…”
Hillenmeyer: Academia's credit-based incentives drive competition and misalignment versus industry
“The currency in industry is, is money or financial, and the currency in academia is credit. And it just leads to interesting incentives. There's a lot of competition. People aren't kind of rowing the same direction all the time. You're trying to take credit ma…”
Hillenmeyer: Female investor representation in biotech is strong and growing
“I actually see a lot of women investors on the biotech side. I think less on the tech side, but I think the numbers are great and growing.”
Hillenmeyer: The antibacterial drug market is broken
“The antibacterial problem is different. Sadly, the market there is just It's broken. Companies know this, the government knows this.”
Hillenmeyer: Drug-resistant bacteria will hit as a massive wave
“The problem is this growing drug resistance in bacteria, they're just swapping these drug resistance genes left and right. It's really scary, and it, it'll, it'll be a massive wave that'll hit us. We just don't quite know when, and investors don't know when th…”