Your High Throughput Screen Isn’t Broken
Originally published on LinkedIn, January 9, 2026
I’ve spent most of the last 20 years building and fixing screens for biotech companies, spanning drug discovery, AgTech, biofuels and biochemicals, and food tech.
One thing I often hear is:
💬 “Our screen isn’t working. We aren’t getting the hits we want.”
But as a great mentor once told me:
🧠 “You always get what you screen for.”
At first glance, that seems obvious. Of course you get what you screen for. But it’s actually a warning.
If you’re not getting the hits you want, it doesn’t mean your screen is broken. It usually means you don’t fully understand what your screen is selecting for.
🧪 A real-world example
Several years ago, I was hired to manage a high-throughput screening group at a biotech company. During interviews and onboarding, I kept hearing the same thing:
“The screen is broken.”
The team was trying to improve the productivity of an organism producing a natural product. Because the product was certified organic, advanced genetic engineering was off the table. Instead, they relied on traditional mutagenesis and screening.
For years, this approach worked. Productivity and titer increased from trace levels to commercially viable ones.
Then the improvements stopped.
Hits looked improved in the HTS but failed to translate in bioreactors.
So my top priority became “fixing” the screen. But you can’t fix something if you don’t understand how it’s behaving.
⚙️ What the screen was actually doing
What we found was simple but critical.
The environments were fundamentally different.
- The HTS ran in 96-well plates with ~200 µL volumes
- No active control of pH or dissolved oxygen
- Endpoint measurements only
The validation step, by contrast, used stirred-tank reactors with controlled pH, dissolved oxygen, and real-time monitoring.
Using tools like RAMOS and PreSens, we discovered that in the plates:
- pH drifted low
- Dissolved oxygen dropped sharply within the first few hours
The screen was doing exactly what it was designed to do, but the design was wrong.
It was selecting for improved mutants under oxygen-limited conditions.
Remove the oxygen limitation, and the improvement disappeared.
🔍 The lesson most teams miss
This is what “you always get what you screen for” really means.
Your screen is not broken. It’s selecting for a condition you didn’t intend.
And this applies to all types of screens:
- Binding
- Immunoassays
- Functional screens
- Phenotypic screens
If the screening environment does not reflect the environment that ultimately matters, the hits will not translate.
🎯 The takeaway
Your high-throughput screen isn’t broken. It’s just telling you something you may not be listening for.