Dr. Maria Waldhoer: Pharmacological Fingerprints and the Limits of Bias

Dr. Maria Waldhoer, CSO of InterAx Biotech AG, argues that endpoint assays — the field's default way of characterizing GPCR ligands — throw away most of the information a compound actually carries. Her team at InterAx models receptor signaling pathways as systems of time-dependent equations, then runs kinetic assays to refine the models and extract ten to fifteen pharmacological parameters from what would otherwise be three endpoint numbers.

The approach sits in deliberate tension with the prevailing vocabulary of bias factors and functional selectivity, and with the common dismissal of HEK293-based work as too artificial to matter. Her answer to that dismissal is partly methodological and partly personal: the proudest moment of her scientific life was designing a compound in a HEK cell from a hypothesis, putting it in an animal, and watching the effect come back exactly as predicted.

The conversation traces her path from neurobiology in Salzburg through academic labs in Vienna, Copenhagen, and Graz, to six and a half years at Novo Nordisk, and into biotech at InterAx — where the next challenge is using functional fingerprints to design ligands, not just describe them.

About the Guest

Dr. Maria Waldhoer is Chief Scientific Officer at InterAx Biotech AG in Switzerland. Her training began in zoology and neurobiology in Salzburg, followed by a PhD on GPCRs in Michael Freissmuth's lab in Vienna and postdoctoral work with Thue Schwartz in Copenhagen and Jennifer Whistler in San Francisco. After running her own academic group in Graz, she spent six and a half years at Novo Nordisk in early drug discovery, focused on incretin receptors. She has been at InterAx since 2017, where she leads the development of a computational systems biology and AI platform that produces time-resolved pharmacological fingerprints of GPCR ligands.

Scientific Themes of the Conversation

• Kinetic versus endpoint characterization of GPCR ligands

• Systems biology modeling of receptor signaling pathways

• Pharmacological fingerprints as multi-parameter compound descriptors

• Ligand residence time as a driver of drug action

• AI combined with functional, not only structural, data

• The academic-to-Big-Pharma-to-biotech trajectory

Key Insights from the Conversation

Endpoint assays collapse the ligand's signature. Standard assay kits that read cAMP at thirty minutes or arrestin recruitment at ten collapse time-resolved signaling into a single number. Dr. Waldhoer argues that most of what distinguishes one compound from another lives in the shape of the kinetics, not the endpoint value.

Model first, pipette second. InterAx treats GPCR pharmacology the way engineers treat aircraft design: build the mathematical model of the signaling pathways first, then use controlled kinetic assays as the "wind tunnel" that refines the model. Inverting the usual order changes what the experiment can be asked to do.

Three inputs can yield fifteen outputs. With a well-constructed computational model and a small set of kinetic assays, one compound on one receptor can be described by ten to fifteen pharmacological parameters — internalization rates, recycling and degradation rates, G protein affinity for the ligand-receptor complex, and more — rather than a single EC50 or a single bias number.

The HEK293 cell earned its keep. Her most formative scientific moment was designing a compound in HEK293 cells from a hypothesis at Novo Nordisk, putting it in an animal, and watching the effect come back exactly as predicted. The "artificial system" critique misses what those systems do for people who know how to ask the right questions of them.

Bias factor is a start, not an answer. Functional selectivity has been in the vocabulary since her PhD years in Vienna. Picking a single time point for a single pathway and computing a bias factor captures far less than looking at how several pathways evolve over time — especially for compounds with unusual kinetics.

The next challenge is multi-receptor, multi-disease complexity. With comorbidities and aging populations driving drug discovery, the one-receptor-one-drug frame is increasingly inadequate. The computational tools that now describe single receptors will need to extend to how multiple receptors in the same cell, in a diseased tissue, at a particular age, interact.

Young founders should not build alone. The hardest-won lesson of her biotech years: great science does not rescue a company from inexperienced management. Scientists starting companies need experienced operators around them, and the honesty to know when to bring them in — a theme she returns to as her farewell message.

Episode Timeline

Timestamps were generated using AI for readability.

• 00:00 — Opening: end-of-2020 wrap-up, January break, announcements

• 01:28 — Meet Dr. Maria Waldhoer, CSO of InterAx Biotech

• 02:19 — From zoology to GPCRs: fate, not choice

• 06:48 — Academia to Big Pharma: speed, scale, and decisions from above

• 09:58 — InterAx's pivot from arrestin biosensors to kinetic systems biology

• 14:31 — Why endpoint numbers miss what a ligand is really doing

• 16:40 — AI plus "real intelligence": functional data in drug design

• 21:48 — Comorbidities, aging, and the multi-receptor frontier

• 24:07 — "What endogenous level would you like me to mimic?"

• 25:26 — The HEK293 experiment that predicted the animal

• 31:21 — Tools for the next decade: biosensors, tissues, high-throughput structure

• 38:43 — Career advice for scientists eyeing industry or biotech

• 42:35 — On starting a GPCR company: why not too early

• 57:30 — Aha moments, including the EU grant pitch in Brussels

• 01:01:53 — "You're only as good as the other people you're with"

Selected Quotes

About this episode

Dr. Maria Waldhoer is originally from Austria. She earned her M.Sc. in Zoology and Neurobiology before completing a Ph.D. in Biology and Pharmacology at the University of Vienna. GPCRs led Maria to Thue W. Schwartz’s lab in Copenhagen where she completed her postdoctoral training. After working in the US and at the University in Graz in Austria, Maria worked several years at Novo Nordisk before joining InterAx Biotech in Switzerland as their Chief Scientific Officer. Even though Maria stumbled upon the GPCR field, her 20 years in both academia and in the industry working on GPCRs make her a strong and dedicated scientific leader.

Dr. Maria Waldhoer on the web

• LinkedIn

• InterAx Biotech

• Pubmed

• Dr. GPCR Ecosystem