The race to engineer new knobs for the human brain

I almost dropped my phone when I saw the news that chemogenetics was in human clinical trials. Chemogenetics is a powerful technique that modifies specific neurons so they can be controlled remotely by normally inert drugs. Bryan Roth, one of the technique’s inventors, told the BRAIN Initiative conference audience on August 13th1 that he had found seven ongoing clinical trials of chemogenetics in China. The disclosure set off a flurry of coverage in the trade media: We’re translating our sci-fi basic neuroscience tools to humans! We’re engineering new knobs for biology! We might have new ways of treating epilepsy, Parkinson’s disease, and pain!Chemogenetics and DREADDs (designer receptors exclusively activated by designer drugs) are very cool. Many of you will be familiar with optogenetics, which engineers neurons to respond to light by inserting a gene adapted from a light-sensitive microbe. Chemogenetics is similar in spirit but lets neurons respond to designer chemicals. Once a gene for a synthetic receptor is expressed in a neuron, the neuron can be driven—excited or inhibited—by its designer chemical, creating a genetically-targeted therapy that can be controlled and titrated remotely by taking more or less of the designer chemical.We’ve come a long way towards treating neurological and neurodegenerative disorders since I was in grad school. Back then, we had three tools for affecting the human brain at the source: small molecules (e.g. fluoxetine), electromagnetism (e.g. DBS, tDCS, TMS, ECT), and changing the sensory environment (e.g. psychotherapy). Now we have developed many more: peptides (e.g. GLP-1R agonists like Ozempic), antibodies (e.g. anti-CGRP meds for migraines), focused ultrasound (either high intensity for ablations or low intensity for modulation). Most relevant to this discussion, we have a slew of methods that engineer neurons for therapeutic effect: optogenetics (thus far limited to the retina), chemogenetics, gene-editing therapies, and cell therapies.These latter are different in kind, because they actually change neurons—or add new ones—often irreversibly, in humans. I had been following the DREADD story peripherally, and I learned a lot by digging into papers that discuss the technology and the descriptions of the clinical trials. In this post, I will unpack DREADDs and chemogenetics, describe what those first clinical trials are doing, and how we might improve upon them. In a follow-up post, I will discuss a competing technology, cell therapy, for the central nervous system.Bryan Roth shared this slide at the BRAIN Initiative meeting. Searching through different Chinese clinical trial databases, he found 7 clinical trials for three indications: pain, Parkinson’s disease, and epilepsy. Not all are operating currently; some are pre-recruitment; it adds up to roughly 10 patients. Nevertheless, China is building momentum to advance human chemogenetics.From Bryan Roth’s presentation.How can chemogenetics be useful? Consider epilepsy, an indication targeted by three of the ongoing trials. Epileptic seizures happen when a person gets focal runaway excitation. Uncontrolled epilepsy (i.e. refractory) can severely disrupt a person’s life, exposing them to personal injury during seizures, making it impossible to drive or even stay employed. At worst, refractory epilepsy can be fatal, leading to sudden unexpected death.One way to stop seizures is to decrease overall activity in the epilepsy focus. However, most treatments do this in a much coarser way: they decrease overall activity everywhere in the brain. For example, benzodiazepines (e.g., diazepam, or Valium), which potentiate all GABA receptors in the brain, are used as a first-line treatment to control acute seizures. They cause habituation, dependence, and severe drowsiness. They are untargeted. Wouldn’t it be nice if we had a way to stop runaway excitation by decreasing activity only at the focal point of the epilepsy?DREADDs allow neurons to be modulated by normally inert chemicals. A virus (an AAV) is engineered to infect neuronal cells and transcribe a payload for a designer receptor. This designer receptor is typically derived by slightly editing an existing human receptor. For example, in the ongoing trials, as far as we can tell, the synthetic receptor is hM4Di, a modified version of the human (h) muscarinic (M) receptor of type 4, which normally binds acetylcholine, a neuromodulator critical in attention. hM4Di no longer strongly binds to its native acetylcholine. Instead, it binds to CNO (normally inert) or clozapine and causes inhibition via a second-messenger, G-protein-mediated cascade.A patient gets an injection of the AAV at the focal epileptic point, which requires a small brain surgery. The new gene gets expressed broadly in neuronal cells after some time. At that point, the new receptor is sitting there, doing nothing. However, when a patient takes the right oral drug, it binds to the novel receptor (the new knob); there’s more inhibition, and the seizures stop.Although the results of the ongoing trials are unknown, the logic is sound. Pre-clinical work in non-human primates shows that a similar system (same vector, promoter and drug, but different reporters), was effective at attenuating seizures in motor cortex induced by bicuculline, a GABA antagonist.Zooming out, any disease that could be remediated if cell type X in area Y could be precisely targeted and excited or inhibited is a potential target for chemogenetics. Chemogenetics is potentially safer and more controllable than gene editing because the effect is reversible by discontinuing the medication2. Chemogenetics could be a big deal.[B]y placing the circuit modulation under the control of an exogenous ligand, chemogenetics mitigates the potential risk of overdosage intrinsic to viral-vector mediated gene therapy. —Devenish et al. (2026)Chemogenetics can be very precise. However, the exact therapy being tested now is not as precise as is technically feasible, for reasons I’ll detail later. Why not make it more precise? Is it a big deal? Media, discussions on X, and Claude were pointing in opposite directions, so I decided to investigate. I came away with the impression that these first-gen chemogenetics treatments are not very precise, but precise enough for their purpose. Thinking through claims of precision highlights how next-gen chemogenetics could be safer, more precise, and more effective, expanding the range of addressable diseases beyond life-threatening ones. Chemogenetics in non-human primates and humans is still niche. As they say in AI circles, this is the worst that it’s ever going to be, and the future is bright.From Tremblay (2023). Chemogenetics in primates is tiny.The canonical designer drug in chemogenetics is CNO, which was originally assumed to be natively inert. However, CNO barely crosses the blood-brain barrier in primates, and it gets metabolized to clozapine anyway, so attention has turned to clozapine. Clozapine activates the same receptor, so study designers have relied on clozapine for human studies. However, clozapine is not a designer drug, and it is not inert: it’s an antipsychotic used to treat schizophrenia. It interacts with multiple receptors: 5-HT2A, H1, native muscarinic receptors, alpha-1 adrenergic, and D4.This promiscuous binding is fine if the drug’s binding affinity is much higher for the target receptors than for off-target ones. Clozapine readily binds to the hM4Di receptor, and the studies therefore use low-dose clozapine. As I was reading this, “low-dose” seemed to entail something similar to low-dose aspirin: a quarter or so of the regular dose. I wasn’t able to find the exact dosing for the epilepsy trials, but the dose in the Parkinson’s disease trials is 1% of the therapeutic dose commonly used for schizophrenia (3.125 mg vs. 300-450 mg). As another point of comparison, clozapine is often used in the treatment of Parkinson’s disease-related psychosis at doses of 25-50 mg; at that dose, side effects tend to be mild, mostly drowsiness.The doses of clozapine in these DREADD trials are ultra-low doses; Bryan Roth calls them homeopathic doses, in a tongue-in-cheek way. The studies screen for prior exposure and clozapine-related damage: agranulocytosis, the severe depletion of neutrophils, a type of white blood cell, is an idiosyncratic and dangerous reaction to clozapine. Clozapine-induced agranulocytosis is said to be dose-independent, and has been reported at 25 mg per day. It would be surprising if the incidence were as high at 3.125 mg per day as with the full therapeutic dose for schizophrenia. Nevertheless, the risk requires long-term monitoring.I would therefore characterize clozapine as not ideal, but probably not the bottleneck in this therapy. I was surprised to find that it could, in theory, be swapped for a truly normally inert compound like DCZ without any ill effect. However, DCZ is not approved as a drug anywhere. Using it instead of clozapine would require separate safety trials; for an investigational therapy, stacking multiple sources of risk unnecessarily compounds cost and risk.Abstract from Goutaudier et al. (2019).An alternative would be to use a “gentler” non-designer drug that has had extensive characterization. DPH, better known by its brand name Benadryl, has been proposed as an alternative, though it requires different modifications to the M4 receptor than the one used in hM4Di. This system, which is called GRANPA3, was published in 2026; hence, it could not have been deployed at the start of these trials.hM4Di is 2 amino acids away from the native human M4 muscarinic receptor. This should be viewed as a strength: it minimizes the number of epitopes that could be recognized as foreign by the immune system. By contrast, in optogenetics, the channels are frequently of bacterial origin; they are foreign and can generate immune reactions.However, hM4Di’s resemblance to the native M4 receptor,