Every government official in Massachusetts should be losing sleep over why this $1B lab isn’t being built in Kendall Square and pushing policies to make sure the next one is
(Hint it has everything to do with retaining CS talent in the city in their 20s)
“Biology is Hard” is a versatile concept. It is a simple truth - it IS hard. It is a useful retort to people who treat its challenges cavalierly. But it is also an excuse - used to rationalize rejecting new approaches in favor of repeating the same mistakes and refusing to correct structural problems in the field that have led to repeated failures.
It is very easy to be pessimistic and right.
Most ideas are bad. Most markets are too early, too small, too crowded, too hard. You can build an entire worldview around seeing the flaw first, and be rewarded for it over and over again
But the strange thing about startups is that the only outcomes that matter come from the places where someone was optimistic and right
I used to underestimate how much this matters. But there is a whole world of difference between reacting to the world as it is, and having enough understanding of the world as it is to still stay open to what it could become
Long optimism
Automated liquid handlers for biology are much older than I thought. A rough timeline:
- The 96-well plate is invented in 1951 by a Hungarian physician, Gyula Takátsy, who physically drilled each well out of a plate of Lucite, a type of acrylic.
- John Sever made the first "modern-looking" 96-well plate by punching it directly out of a sheet of plastic.
- The first automated liquid-handling device was released in 1967 (!!!). It was called the Autotiter, and was developed by a man named Tom Astle. I found a few sentences on Astle's company:
"Tomtec has succeeded since 1967 by working with its clients to help solve their liquid handling needs. From 1967 to 1981, the Company had essentially one employee, Tom Astle. From 1967 to 1971, the Company operated as Astec, Inc. In 1971 the Company's name was changed to Tomtec, and incorporated. Tom Astle has been the President and CEO since that time. In 1967, Tomtec developed the Autotiter. This automated what were then the manual microtiter techniques. The primary market was serology and virology. The original instruments were an essential element of Smith Kline's rubella vaccine program." (Photos of the original patent filing below.)
- In 1986, Beckman gets into the microplate automation space. They release the Biomek 1000 and mark it as a "fast and accurate...robotic workstation" that sits on a scientist's bench, "takes over tedious manual tasks and integrates the work of four different instruments." I found these details in a Beckman ad, which was published in a 1987 issue of the "Journal of Automatic Chemistry." Photos below.
The Beckman device looks fully modern; it could even connect to an IBM computer so scientists could program new methods on it. I couldn't find a launch price, but the device was similar to the Zymark Zymate, and that device cost about $35,000 when it released in the 1980s, which would be equivalent to hundreds of thousands of dollars today.
Are therapeutics startups the crabs of the biotech world?
In evolutionary biology, there's a phenomenon called carcinization, where different species, again and again, independently evolve into something that looks like a crab.
It's happened at least 5 times.
🧵 (11)
Congrats to @scribetx and @CIRMnews!
And a thoughtful analogy from @BenjaminLOakes below. If the genetic medicine could be safe enough and effective forever — we would all want the one-time genetic upgrade.
I love that this goal is both audacious and also extremely plausible for humanity to achieve. Much of the science is already here; we just have to roll up our sleeves for a few years and get it done.
CRISPR genetic medicines are often described as more “convenient” than chronic treatments like pills or injections. 𝗜 𝘁𝗵𝗶𝗻𝗸 𝘁𝗵𝗶𝘀 𝗺𝗶𝘀𝘀𝗲𝘀 𝘁𝗵𝗲 𝗽𝗼𝗶𝗻𝘁 𝗲𝗻𝘁𝗶𝗿𝗲𝗹𝘆.
𝗜𝘁 𝗶𝘀 𝗹𝗶𝗸𝗲 𝘀𝗮𝘆𝗶𝗻𝗴 𝗳𝗹𝘆𝗶𝗻𝗴 𝗮𝗰𝗿𝗼𝘀𝘀 𝘁𝗵𝗲 𝗰𝗼𝘂𝗻𝘁𝗿𝘆 𝗶𝘀 𝗺𝗼𝗿𝗲 𝗰𝗼𝗻𝘃𝗲𝗻𝗶𝗲𝗻𝘁 𝘁𝗵𝗮𝗻 𝘄𝗮𝗹𝗸𝗶𝗻𝗴. 𝗧𝗲𝗰𝗵𝗻𝗶𝗰𝗮𝗹𝗹𝘆 𝘁𝗿𝘂𝗲, 𝗯𝘂𝘁 𝘄𝗶𝗹𝗱𝗹𝘆 𝗶𝗻𝗰𝗼𝗺𝗽𝗹𝗲𝘁𝗲. One is not just an easier version of the other. Flying makes the journey possible for everyone, while only a select few could ever hope to complete a cross-country trek.
We see this same dynamic play out again and again in cardiovascular disease. The current standard of care asks patients to commit to chronic therapy for decades: daily pills, repeat injections, and continued persistence fails for most. 𝗜𝗻 𝗿𝗲𝗰𝗲𝗻𝘁 𝘀𝘁𝘂𝗱𝗶𝗲𝘀, 𝗺𝗼𝗿𝗲 𝘁𝗵𝗮𝗻 𝟳𝟬% 𝗼𝗳 𝗽𝗮𝘁𝗶𝗲𝗻𝘁𝘀 𝘄𝗲𝗿𝗲 𝗻𝗼 𝗹𝗼𝗻𝗴𝗲𝗿 𝘁𝗮𝗸𝗶𝗻𝗴 𝘁𝗵𝗲𝗶𝗿 𝘁𝗵𝗲𝗿𝗮𝗽𝗶𝗲𝘀 𝗮𝗳𝘁𝗲𝗿 𝗼𝗻𝗹𝘆 𝗮 𝗳𝗲𝘄 𝘆𝗲𝗮𝗿𝘀.
Against that backdrop, describing durable genetic medicines as simply more “convenient” does no one justice. The current chronic medication paradigm, our “sick-care” framework, simply does not work well enough for silent lifelong diseases such as CVD.
𝗪𝗲 𝗺𝘂𝘀𝘁 𝗯𝘂𝗶𝗹𝗱 𝘀𝗼𝗺𝗲𝘁𝗵𝗶𝗻𝗴 𝗯𝗲𝘁𝘁𝗲𝗿. The goal is not just fewer doses. The goal is a model of prevention that is practical for all and matched to how lifelong risk actually works.
𝗪𝗲 𝘀𝗵𝗼𝘂𝗹𝗱 𝗻𝗼𝘁 𝘀𝗲𝘁𝘁𝗹𝗲 𝗳𝗼𝗿 𝗺𝗮𝗸𝗶𝗻𝗴 𝘁𝗵𝗲 𝘄𝗮𝗹𝗸 𝗲𝗮𝘀𝗶𝗲𝗿. 𝗪𝗲 𝗺𝘂𝘀𝘁 𝗯𝘂𝗶𝗹𝗱 𝘁𝗵𝗲 𝗮𝗶𝗿𝗽𝗹𝗮𝗻𝗲.
I am incredibly proud that the California Institute for Regenerative Medicine is helping us make that vision a reality. Scribe recently announced that we have been awarded more than $25 million from CIRM to help advance STX-1200 for Lp(a) and STX-1400 for severely elevated triglycerides toward the clinic.
This funding helps us move these programs from possibility to patients.
𝗖𝗼𝗻𝗴𝗿𝗮𝘁𝘂𝗹𝗮𝘁𝗶𝗼𝗻𝘀 𝘁𝗼 𝘁𝗵𝗲 𝗦𝗰𝗿𝗶𝗯𝗲 𝘁𝗲𝗮𝗺, 𝗮𝗻𝗱 𝘁𝗵𝗮𝗻𝗸 𝘆𝗼𝘂 𝘁𝗼 𝗖𝗜𝗥𝗠 𝗳𝗼𝗿 𝘀𝘂𝗽𝗽𝗼𝗿𝘁𝗶𝗻𝗴 𝗼𝘂𝗿 𝗺𝗶𝘀𝘀𝗶𝗼𝗻 𝘁𝗼 𝗯𝗿𝗶𝗻𝗴 𝗱𝘂𝗿𝗮𝗯𝗹𝗲 𝗴𝗲𝗻𝗲𝘁𝗶𝗰 𝗺𝗲𝗱𝗶𝗰𝗶𝗻𝗲𝘀 𝘁𝗼 𝗽𝗮𝘁𝗶𝗲𝗻𝘁𝘀 𝘄𝗶𝘁𝗵 𝗰𝗮𝗿𝗱𝗶𝗼𝗺𝗲𝘁𝗮𝗯𝗼𝗹𝗶𝗰 𝗱𝗶𝘀𝗲𝗮𝘀𝗲.
Incredibly important initiative. We have massively underestimated the criticality of so-called minor viruses in driving chronic illness.
From the blog post:
“Respiratory infections raise our risk of serious illness, often years later. While researchers are still early in establishing these connections, it seems plausible that society has meaningfully underestimated the significance of seemingly benign infections on short and long-term health, e.g.:
- 9.8x asthma risk by age 6 if infected with HRV between birth and age 3 in a high-risk cohort
- 6.1x heart attack risk for 7 days after influenza infection
- 4.5-5x dementia risk after severe influenza
- 2.6-4.1x Alzheimer’s risk after severe influenza and pneumonia
- 2.2-3x schizophrenia potential riskfor infant if mother is infected by influenza during pregnancy
-1.3x risk of heart failure after RSV infection compared to influenza”
much of the US-China biotech debate talks past the core tradeoff:
patients are not best served by maximizing the number of near-term in-licenses if doing so weakens America’s domestic capacity to discover, develop, and manufacture future medicines.
Best drugs are rarely the first drugs. Patents are published so others can improve. Courts resolve questions of infringement.
Cures aren’t weapons. In this race, when someone else succeeds, you still win.
Most are game to compete. Only a few whine & ask for special treatment.
American biotech VCs: remember your place in this ecosystem.
You are not pharma. A sleepy R&D org with a patent cliff bearing down has every reason to grab a cheap Chinese GLP-1++ and call it a day - *fine*, that's what late-stage capital is for. But you took a different job. Your contract with the people upstream of you is to eat *more* risk than they will, so they never have to wear a loss on their balance sheet.
You're their wine taster. You're supposed to be hunting the next Boger/Vertex, the next Kevan Shokat/RevMed - to be the Brook Byers to a Ted Greene who drags the first GLP-1 across the FDA line. The next Cobenfy. The next Casgevy.
You are not a house flipper. While ferrying cross-border Kailera-style vehicles is helping you juice your DPI and feels great in the short term, it's eating your seed corn. Yes, some of these Chinese NMEs are truly me-better drugs (ivonescimab beat Keytruda, no need to remind us of that!). But as a *strategy* they're Cheetos - everyone's eating from the same bag, and the day it's stripmined, there will be nothing proprietary left in your orange corn starch stained fingertips. Meanwhile -- uh oh -- looks like nobody planted the seedlings of that next generation of American biotech, and you'll be squarely to blame for neglecting it on short term opportunity cost alone.
Perhaps you should've gone for the trail mix. Mostly cashews and almonds, sure. But every so often you get an M&M...
Satya Nadella talks about the token economy. Dario Amodei predicts an abundance of new drugs thanks to AI agents.
As tokens and agents transform the economics of entire industries, what makes genetic medicine particularly well-positioned to benefit from industrial-scale reasoning? Modularity. Every component, including operational workflows, can be optimized, de-risked, and improved independently, then reused across programs.
In a new Substack post, we describe how we’re collaborating with @NVIDIAHealth to build a new infrastructure stack for genetic medicine – lowering the barriers to entry for drugs that were once considered economically infeasible.
Read more: https://t.co/Zr2MqoHfoq
Finally got a good plan for replicating my favorite Mirabilis jalapa patterning! Using Ds/Ac transposase system to mess with the glucosyltranaferase in RUBY for lovely sectoring. Lots of classical gene mods to follow. Lots of fun attempts this summer. 🤞🤞
The FDA has announced a pilot aimed at faster Phase I trials in the United States. I have written at length about the major positive implications such a policy would have and I am glad to see this happen.
Speeding up Phase I trials NOW is important for several reasons:
1) The importance of Phase I trials in the drug development pipeline (they bottleneck everything else) and for learning: given that this is the first time drugs are entering humans, this is a stage that provides critical information and enables iterative learning.
2) China's looming threat to US biotech, largely driven by their ability to generate first-in-human (FIH) evidence faster.
3) Small biotech companies, which generate most medical innovation now, pass through a "Valley of Death" before Phase I trial results. This is a period of time when running out of funding is especially likely and when the uncertainty associated with in vitro data means that investors have limited high-quality information regarding which companies they should invest in. Once a company has positive first-in-human data, a positive flywheel effect is generated, whereby attracting investor interest becomes easier.
Overall, faster and more efficient Phase I clinical trials means that we can iterate on human data better and investors can make better decisions and pick the *right* winners. It is also a critical biosecurity measure, as a strong biotech sector will be critical to avoiding pandemic and bioweapon threats.
https://t.co/SkjdPuZjJA
While my cancer has been undetectable for over a year, we stay paranoid.
I'm now on my fifth personalized cancer vaccine. Alongside monthly MRD monitoring, we use deep immune profiling to track how each dose reshapes my immune landscape and optimize future formulations. Will Hudson at Baylor built the approach combining flow cytometry (30+ surface markers) with single-cell TCR sequencing on blood samples. Two findings stand out:
1. Sustained immune activation compared to healthy donors, consistent with ongoing immunotherapy and vaccine response
2. A distinct CD39+ CD8+ T cell population persisting at elevated levels, showing signs of antigen experience and preferential binding to anti-PD-1 antibodies — suggesting active tumor surveillance
The big open challenge is deorphanizing TCRs — matching receptors to their target epitopes — to understand which mutations are being actively patrolled and which need reinforcement in future vaccines. All data is publicly available at osteosarc dot com (link in comments). If you work on TCR-epitope matching or epitope-reactive clonal dynamics, we'd love your help finding patterns we're missing.