Summary.

We are working on in-adult replication of the existing human short sleeper phenotype, hosted at Harvard Medical School. This could safely decrease sleep needs in adults. It could potentially help healthy people sleep less, and also impacting narcolepsy, Alzheimer's and longevity.

Abstract.

We spend one-third of our lives asleep. Yet, a small subset of individuals thrive on four to six hours of sleep per night. They carry short sleeper gene variants, allowing them to remain healthy while sleeping less. Researchers report those short sleepers to have more energy, vigor, and disease resistance than baseline, indicating that the same gene variants compress sleep and improve daytime quality of life. (1, 2, 3, 4, 5)

Our project aims to use these naturally occurring mutations to develop a targeted therapy that safely decreases sleep need while preserving health. The main roadblocks are delivery past the blood-brain barrier and safe targeted modification.

Overcoming these barriers, the main open empirical question that could be detrimental is whether those short sleeper genes are required during childhood. Neurodevelopmental necessity is the most likely reason this fails. If that's the case, then we will prove the negative. Other failure modes are difficulty in sufficiently broad brain delivery or editing problems.

Preliminary studies show introducing human short sleeper variants into mice is safe and effective at an embryonal stage. (1,2,3) Lifelong, the mice sleep less  while remaining healthy. This suggests that shorter, higher-quality sleep can be both beneficial and sustainable. We hope to develop a therapy which can induce the same beneficial changes with a single administration in adults. We will initially target DEC2 and ADRB1 gene variants. We will use base editors delivered by adeno-associated viruses to introduce short-sleeper variants into adult mice. We will validate introduction by sequencing, and measure changes in sleep duration, sleep quality, activity, and behavior.

Potential.

Ozempic is shaping up to be one of the most impactful therapies of the decade, by directly modulating hormonal biophysical pathways. Analogously, modulation of DEC2 and orexin may illuminate how key pathways regulate sleep, and allow us to engineer safe approaches to waking hours without the detrimental effects of sleep deprivation, in both diseased and healthy states.

An initial prototype is likely to look a lot like a semi-perminanent "vaccine for sleep", whereas a large-scale market version would likely need to be a small-molecule drug. Thus the "ozempic for sleep" metaphor.

First, the most obvious benefit is the amount of wake hours regained by healthy individuals, as well as potential gains in daily well-being. Downstream, this could translate to increased productivity in individuals, small groups, and at sufficient scales even in economies. Imagine only sleeping 4 hours a night yet feeling well-rested and energized during the day, in addition to the time added to life. Compressing sleep by 2-4h per night directly adds 6-13 years to a life: If safely compressing sleep to 4h is possible, that directly pushes effective lifetime to a ~100 year lifespan equivalent. (80y lifespan/8h asleep is 53y awake; 80y/4h gives 66 wake-years, same as 100y/8h.)

Besides the benefits of requiring less sleep and broad health improvements, humans and mice with these genotypes seem more resistant to neurodegeneration. Low rates of neurodegenerative diseases in short sleeper families have been noted by researchers and subsequent short sleeper mice show hat  to Alzheimer disease pathologies, with reduced accumulation of beta-amyloid and tau plaques. (6, 7, 8)

Narcolepsy is a debilitating disease affecting 3 million people worldwide, often caused by orexin dysregulation. Prof. George Church also suffers from narcolepsy. Previous proof-of-concept work has shown the feasibility of orexinergic therapies treating narcolepsy. (10, 11, 12) Modulation of the DEC2 genes could restore orexin levels safely. This therapy could both enhance daily functioning and slow the progression of diseases. It may serve as a prophylactic to lower narcolepsy and Alzheimer risk. 

Funding.

Funding will enable the first few iterations of these feasibility experiments and towards creating a proof-of-concept in-adult "sleep vaccine". It will go to wet lab costs, transgenic mice, lab tech and PhD salaries, sequencing cost of short-sleeper individuals, contracting CROs for adenoviruses, and more. We were recently supported by an Emergent Ventures grant from Tyler Cowen (~25k). We have an additional ~$75k in private funder commitments. This leaves a gap of ~$100k towards the fundraising goal of $200k to support the effort for 1-2 years.

Team.

Isaak Freeman. Isaak is a grad student at Ed Boyden's lab at the McGovern Institute, MIT. Isaak skipped out of high school on his state's prodigy program. At age 19 he ran a non-profit which hosted a crossover conference between academia and technologists hosting guests like 3Blue1Brown, Holden Karnofsky, Daniela Amodei, Sam Altman and Ed Boyden. Isaak previously studied applied math at Berkeley and worked in neuroimmunology at Oxford. Isaak first sketched out the idea for an "sleep vaccine" in this blog post.

Helena Rosengarten. As a soon-to-be MD-PhD, Helena previously worked at Harvard Medical School on rare genetic disease treatments and brings required expertise for in-vivo editing platforms. Currently at Charité Berlin, she holds Germany's Studienstiftung scholarship. Helena previously brings in experience as a research associate at a preventive medicine & longevity company.

Siddarth Lyers. Siddarth knows how to get things into mouse brains. He graduated in materials science and biomaterials engineering from Johns Hopkins and is pursuing a PhD at MIT. A visiting graduate student in the Church Lab, he is advancing viral RNA delivery for gene-editing therapeutics, currently with virus-like particles for delivery. A 2021 NSF Fellow, he is excited to use his genetic tool experience for the sleepless project.

Dr. George Church. Known as the founder of modern-day synthetic biology and genomics, George is a professor at Harvard Medical School, where he has catalyzed breakthroughs in genome sequencing and gene editing. George earned his PhD under Harvard Nobel Laureate Walter Gilbert, and helped launch the Human Genome Project, for which he developed methods for genome sequencing. The Church lab is one of the most successful moonshot ideas to start-up incubators in translational biology. George also personally suffers from narcolepsy. 

Dr. Fei Chen, advisor. Fei is an assistant professor at Harvard and the Broad Institute. During his PhD at MIT, he co-invented expansion microscopy with Ed Boyden, a breakthrough enabling super-resolution imaging using standard microscopes. His lab at Harvard develops cutting-edge spatial genomics tools like Slide-seq to map gene expression with cellular resolution. Fei is interested in building tools for modulating physiological states: Like GLP-1 agonists modulate hungry vs fed states, Fei wants to develop tools that modulate sleep needs.

Bibliography.

(1) Hirano, A. et al. (2018). DEC2 modulates orexin expression and regulates sleep. Proceedings of the National Academy of Sciences of the United States of America, 115(13), 3434. 

(2) He, Y. et al. (2009). The Transcriptional Repressor DEC2 Regulates Sleep Length in Mammals. Science, 325(5942), 866. 

(3) Shi, G. et al. (2021). Mutations in Metabotropic Glutamate Receptor 1 Contribute to Natural Short Sleep Trait. Cell: CB, 31(1), 13–24.e4. 

(4) Shi, G. et al. (2019). A rare mutation of β1-adrenergic receptor affects sleep/wake behaviors. Neuron, 103(6), 1044. 

(5) Beck, M. (2011). The Sleepless Elite. The Wall Street Journal. 

(6) Ying-Hui Fu, personal communications.

(7) Dong, Q., Ptáček, L.J., & Fu, Y. (2023). Mutant β1-adrenergic receptor improves REM sleep and ameliorates tau accumulation in a mouse model of tauopathy. PNAS, 120. 

(8) Dong, Q. et al. (2022). Familial natural short sleep mutations reduce Alzheimer pathology in mice. IScience, 25(4). 

(9) Sakurai, T. (2013). Orexin deficiency and narcolepsy. Current Opinion in Neurobiology, 23(5), 760-766. 

(10) Kantor, S. et al. (2013). Orexin Gene Therapy Restores the Timing and Maintenance of Wakefulness in Narcoleptic Mice. Sleep, 36(8), 1129. 

(11) Mitsukawa, K. et al. (2024). TAK-861, a potent, orally available orexin receptor 2-selective agonist, produces wakefulness in monkeys and improves narcolepsy-like phenotypes in mouse models. Scientific Reports, 14(1), 1-15. 

(12) Arias-Carrión, O., & Murillo-Rodríguez, E. (2014). Effects of hypocretin/orexin cell transplantation on narcoleptic-like sleep behavior in rats. PloS one, 9(4), e95342.