Lester Research Group
iNicSnFR3a/12
Our lab's current research focus is on nicotine addiction, the world's largest preventable cause of death. Now we are developing continuous nicotine monitor (CNMs) for personal nicotine pharmacokinetics. It's a "receptor-aware" research agenda, meaning that we wish to understand the dynamic nicotine concentration [nicotine]t, faced by high-sensitivity nicotinic acetylcholine receptors (nAChRs) in the brain of individual human subjects during and after nicotine intake.
We have several motivations for this research agenda. First, "Know the potential enemy at an individual level". Smoking or vaping produces an initial "bolus" of nicotine in the blood and brain, lasting ~5 min with a peak concentration of ~ 100-200 nM. The bolus largely governs reinforcement, reward, and cognitive enhancement. A prolonged declining phase of [nicotine], with a half-time of 1 to 4 h, largely suppresses withdrawal symptoms and governs the known cell biology of addiction.
Another motivation is to "know the potential therapy", because individual [nicotine]t records will be useful during research on the effectiveness of nicotine replacement therapy. A final motivation is to "know the physiology". The only known effects at the relevant [nicotine]t occur at nAChRs in cerebrospinal fluid (CSF). The three effects are activation, desensitization, and chaperoning/upregulation. Therefore, additional mechanistic insights will arise from correlating [nicotine]t with readily measurable physiological data on those effects in molecular, cellular, and brain slice systems and animal models.
Interstitial fluid is the appropriate compartment for a CNM. The molecular sensor technology could employ fluorescence, as shown by our progress on measuring [nicotine]t with improved variants of intensity-based nicotine-sensing fluorescent reporters (iNicSnFRs). Electrochemical measurements of [nicotine]t may also be possible. Studies like Population Assessment of Tobacco Health would contextualize [nicotine]t measurements during each subject's ad libitum nicotine intake, hopefully at a cost < $100 for a 24-hour record. The collaborative research agenda culminating in a CNM must use public funding.
At Caltech, the CNM research represents a collaboration across three Divisions and include Professors Steve Mayo, Dennis Dougherty, and Wei Gao. We have learned how to improve the nicotine sensitivity of iNicSnFRs by a LIGO-like factor of 106 and how to embed the iNicSnFR molecules in a hydrogel that permeates nicotine but allows us to isolate nicotine from other, interfering molecules.