ZeClinics

How do you link a disease phenotype to the exact genes driving it? A biotech partner came to us with that exact challenge in Parkinson's disease. We used a single model: zebrafish larvae from the HuC:Gal4;UAS:DsRed transgenic line, treated with MPTP to reproduce dopaminergic neuron loss and locomotor impairment. The fluorescent label lets us isolate those exact neurons later for RNA sequencing. Here's how fast it moved: ↳ Day 5: a fully validated zebrafish Parkinson's model, confirmed by dopaminergic neuron loss and locomotor deficits. ↳ Week 6: mechanistic, pathway-level readouts from RNA sequencing of the isolated neurons. The results: ↳ MPTP-treated larvae showed a clear reduction in TH1-positive dopaminergic neurons versus wild-type controls. ↳ Significant locomotor deficits across light and dark phases, confirmed by automated video tracking ↳ Neuronal RNA sequencing identified numerous differentially expressed genes, revealing the molecular pathways behind the observed phenotype. A rescue compound tested in this same setup induced partial recovery of the control phenotype. The same workflow can screen any candidate molecule. Connect with me and comment "Parkinson" below to get the case study.

Why does the FDA consider zebrafish a NAM? In March 2026, the FDA issued a draft guidance about General Considerations for the Use of New Approach Methodologies in Drug Development, in which zebrafish were explicitly mentioned as an example. The FDA considers zebrafish a NAM because they fit the agency’s broader push toward methods that are more efficient, mechanistically informative, and less dependent on traditional mammalian testing. They bridge in vitro assays and mammalian in vivo studies, preserving whole-organism biology that cell systems miss. Early zebrafish embryos and larvae also align with the 3Rs framework because they reduce and refine the use of higher-order vertebrates. In fact, embryos up to about 120 hours post-fertilization are not treated as protected animals under European rules. A great example is that within FDA drug submissions, zebrafish dominate the nonhuman in vivo NAM category (https://lnkd.in/ewXdJk-b). This shows that the Center for Drug Evaluation and Research (CDER), a part of the FDA that regulates over-the-counter and prescription drugs, already treats them as part of the NAM landscape. None of this makes zebrafish a replacement for mammals or settles the NAM versus animal model debate once and for all. It settles for a specific set of questions, at a specific resolution; this 5-day-old larva already answers what the FDA needs to know. Context of use, not category, is what decides that.

Zebrafish can tan. Not on a beach, but the biology checks out. The pathways regulating melanocyte development, differentiation, and pigmentation are highly conserved between zebrafish and humans. Human and zebrafish melanocytes even share a common origin, arising from the neural crest and relying on the same developmental genes, including sox10, wnt, and kit signaling. What makes this genuinely useful for research is the transparency. Zebrafish larvae allow direct, label-free imaging of melanin production and distribution within days. We built our pigmentation model around exactly this. Larvae are exposed to test compounds during defined developmental stages; we evaluate pigmentation patterns through high-throughput imaging and quantify melanin content. It supports: → Early screening for compounds that stimulate or inhibit melanogenesis. → Evaluation of cosmetic ingredients targeting skin tone, hyperpigmentation, or depigmentation. → Mechanistic or target validation work on pigmentation pathways. Contact us for more info on how to accelerate cosmetic and dermatology compound screening with zebrafish: https://lnkd.in/dpQGHRz

See you next week. Part of our team will be in Vienna from September 13 to 16, at the Austria Center Vienna, alongside a large part of the European toxicology community. "Toxicology without borders" is the theme of the event and is close to how we think about zebrafish in the first place: a model that keeps proving it belongs in conversations that used to be reserved for mammalian systems. Let's have those conversations on how zebrafish can help de-risk a drug candidate or clear a chemical safety hurdle. And if you are specifically interested in PROTACs, let's meet for sure. We are presenting a poster on the validation of zebrafish for toxicity profiling of IMiDs and PROTAC compounds in collaboration with HESI. Don't miss it! If you will be there too, our team would like to say hello.

Zebrafish untangled the connection between antipsychotic drugs and ALS. In a study by Patten et al., zebrafish models were employed to evaluate the efficacy of pimozide, a decades-old antipsychotic, for ALS. The zebrafish used in this study carried mutations in the Sod1 gene, which is commonly associated with familial ALS. These mutant zebrafish exhibited hallmark ALS symptoms, including motor neuron degeneration and impaired swimming. Treated zebrafish showed more robust neuromuscular junctions, better synaptic transmission, and less muscle denervation than untreated controls. The proposed mechanism ties back to calcium homeostasis. Pimozide appears to modulate calcium channels in neurons, helping guard against the excitotoxicity thought to drive ALS progression. This preclinical evidence complemented the registration of a Phase II clinical trial (NCT03272503), although the current status of the trial remains unknown. At ZeClinics, we have built a CNS model portfolio to help researchers screen compounds with shorter turnaround times compared to mammalian models. We are currently developing models for ALS, but our ready-to-use models cover epilepsy (PTZ pharmacological, scn1lab and gabra1 genetic) and Parkinson's disease (MPTP). For programs targeting other indications, we generate custom CRISPR lines. If your pipeline could use a faster CNS screen, let's talk.

100,000 neurons are all it takes. The human brain is large, on average 86 billion neurons, anatomically difficult to access through the skull, ethically complex to justify invasive studies, and biophysically challenging to investigate with non-invasive methods. The mouse brain, at approximately 70 million neurons, is still too large to visualize in its entirety without removing the brain and examining sections or using disruptive clarity approaches. The larval zebrafish brain contains approximately 100,000 neurons. Still, the 100,000 neurons within the zebrafish larval brain provide: → The same major structural regions as the human brain. → The same principal neurotransmitters as in mammals (glutamate, GABA, and glycine). → Highly conserved receptors and transporters. This simplicity reduces the search space for identifying disease-associated circuit changes. Most of these neurons are individually identifiable across animals, enabling the monitoring and manipulation of the same neural connections in wild-type and disease models. Researchers from the Max Planck Institute have created a zebrafish cerebral atlas to provide the field with standardized brain region annotations, traced single neurons, and a compendium of markers and transgenes. Check it out: https://lnkd.in/g9DE3J2e Small brain. Big insights.

A wounded zebrafish tail can give us lots of information. When you clip the tail fin of a zebrafish larva, the immune system responds. An acute local inflammatory response induces the accumulation of macrophages and neutrophils near the wounded area. It is a quantifiable readout for anti-inflammatory drug discovery, since the innate immune pathways are highly conserved between zebrafish and mammals. For our injury inflammatory model, we use the Tg(mpx:mcherry) reporter line for neutrophils and clip the fin at early developmental stages. The larva is transparent. That means we can image the entire process in a living animal, in real time. After wounding, we image at defined timepoints and count neutrophil recruitment directly at the injury site. This format is compatible with multi-compound screening. You prioritize anti-inflammatory candidates early, in vivo, at a fraction of the time and cost of rodent studies. The tail can grow back, by the way. Are you reassessing your preclinical strategy? Let's talk!

This is a complete vertebrate organism that fits in a well. What you see in the video is a zebrafish larva. At early developmental stages, before day 5 post-fertilization, it measures around 2-3 mm. Small enough to fit in a well, complex enough to model human disease. Because it fits in a well, you can run dozens of experiments in parallel, one larva per well, under controlled conditions, with automated tracking. At those early stages, that larva already has: → A functional cardiovascular system. → A developed nervous system. → A liver processing compounds. → Eyes capturing light and driving behavior. In drug discovery, the gap between in vitro and mammalian models is where programs slow down, and costs accumulate. Zebrafish close that gap.

The way we give drugs to zebrafish might be affecting the results. Two methods dominate compound administration in adult zebrafish: waterborne exposure and oral gavage. In waterborne exposure, the compound is dissolved in the water, and the animal absorbs it passively. It is simple, but determining the actual concentration inside the animal requires expensive and time-consuming chemical analysis. Oral gavage offers more control over dose and timing, but most studies use anesthesia to immobilize the animal during the procedure. Anesthesia can cause cardiovascular, respiratory, and behavioral disruptions. The handling involved can also lead to lesions. In other words, the intervention meant to deliver the compound cleanly may be introducing noise into the very data it is supposed to generate. Our team evaluated and enhanced a recently developed anesthesia-free gavage technique to address this. We applied it to administer daily estradiol doses to adult zebrafish for 40 days to evaluate reproductive toxicity. Results showed that neither estradiol administration nor the gavage method caused stress or injury, but both impacted reproductive capacity in a dose-dependent manner. ✅ No stress for the animals and a validated DART model for reproductive toxicity studies. Read the full paper: https://lnkd.in/dH5UfXqH

The best ecotoxicology models are the ones you can see through. Literally. Zebrafish larvae are transparent. So is Daphnia magna, a freshwater crustacean of 1-5 mm that most people outside ecotoxicology have never heard of. That transparency is part of what makes both organisms so useful. You can observe internal organs, physiological responses, and behavioral changes directly, in a living animal, without any invasive preparation. But there is another reason Daphnia earned its place as the standard model for acute aquatic toxicity testing. It sits at a critical position in aquatic food webs, between algae and fish. If a chemical compound affects Daphnia, the consequences can propagate throughout the aquatic environment. Add to that its extreme sensitivity to chemical exposure, its short life cycle, and the ease of culturing it under standardized lab conditions, and you have an organism that regulators have trusted for decades. The OECD TG 202 captures that. At ZeClinics, zebrafish will always be our first love. But transparency, it turns out, runs in the family. Send me a message for more information on this test. 🔬 Daphnia giving birth. Image credit: MarekMiś