Somna: Leveraging Chemogenetics to Maximize Sleep Quality and Minimize Sleep Time
Over 65% of people across the United States wake up in the morning feeling tired and sleep-deprived. Whether you’re a student who has to study for finals, a new parent who needs to take care of a newborn baby, or you have trouble falling asleep due to stress, sleep is vital for your health. The recommended amount of sleep for adults is 8 hours, meaning that we spend around 1/3 of our lives asleep. Even with a full 7–8 hours of sleep, it doesn’t guarantee that you feel well-rested and refreshed for the next day.
Current sleep solutions such as sleep medicine can induce sleep but lead to drowsiness the next morning and caffeine is only a short-term fix to sleep deprivation. Other tools such as sleep trackers or noise-canceling sleep aids may provide information to improve your quality of sleep, but they do not cut down on the amount of time you need to sleep.
What if there was a way we could get a restful night of sleep and feel energized in half the time?
Somna is a moonshot company that is working towards creating a future where everyone can get the same benefits of 8 hours of sleep but in half the time. Our sleep solution involves a two-part process that includes a noninvasive surgery and a nightly ionized water solution.
A Short Primer on Sleep
Every night, the average person goes through four to six sleep cycles, roughly about 90 minutes each. Each sleep cycle has a different focus, with the first two to three cycles focused on deep Non-REM sleep, while the final sleep cycles are centered more on REM sleep. NREM and REM sleep are the main parts of our sleep cycle that allow for important processes such as brain repair and memory consolidation. NREM, in comparison to REM, uses less energy.
During NREM sleep, cortical slow oscillations of the neurons occur, allowing the interconnection of neural networks that lead to information processing, synaptic plasticity, and neural plasticity. This means that during NREM sleep, neurons are actively forming new connections.
Within NREM sleep, there are three separate stages. The first stage of NREM sleep is extremely light sleep during the first ten minutes of your cycle. The second stage of NREM sleep relaxes the muscles and begins slow brain waves for roughly 30 to 60 minutes. This then leads to Slow Wave Sleep (SWS), also known as deep sleep, which is vital for memory consolidation.
After SWS, REM sleep occurs when the brain is in a state of stabilization. During this period, less important neural connections are filtered out, thus allowing the more important neural connections to be strengthened and fortified.
Both REM and NREM sleep are integral parts of the human sleep cycle. NREM sleep allows the production of new neural pathways while REM sleep solidifies these connections.
REM and NREM sleep reoccur throughout every sleep cycle, roughly around four to six times per night. However, in between these sleep cycles, it is very common for people to unconsciously wake up between these sleep cycles, which can fragment sleep and reduce sleep quality. Thus, Somna focuses on cutting out the number of sleep cycles necessary each night in order to minimize wake-up times while lengthening time spent in REM and NREM. As a result, this cuts out the intermediate stages between REM and NREM, which can cut down on sleep time.
Chemogenetics is a technology that involves the use of biomolecules that are engineered to interact with other specific biomolecules. Currently, this technology is used in neuroscience labs across the country to study the brain and control the expression of target neurons.
Chemogenetics involves two components: a receptor and a ligand. Receptors are proteins that can receive signals (i.e. hormones, antigens, ligands, etc.) while a ligand is a substance that binds to biomolecules (such as receptors) that can generate a biological response. You can think of it like a lock and key, where the ligand is the key and the receptor is the lock.
The synthetic ligand is only able to interact with its target receptor in the same way that a key is only able to open the specific lock that it corresponds to. Similarly, the genetically engineered receptor is not able to interact with any other biomolecules that are located in the body, so in the case where the ligand is not present, it will not elicit a biological response.
Somna’s solution involves inserting genetically modified neuron receptors that are only able to respond to a synthetic ligand called clozapine nitric-oxide (CNO). Once CNO binds to the receptor, it will unlock the mechanisms responsible for regulating sleep.
Targeting Sleep-Regulatory Neurons
The neurons we plan on targeting are Parafacial Zone (PZ) GABAergic neurons, Ventral Tegmental Area (VTA) Dopaminergic neurons, and glutamatergic neurons. The PZ GABAergic neurons are responsible for helping the brain enter NREM, VTA dopaminergic neurons can promote sleep-related behavior when inhibited, and the glutamatergic neurons help the brain enter REM.
Activating PZ GABAergic neurons can induce short-wave sleep (SWS), increase SWS amount, and improve slow-wave activity (SWA) — which serves as a metric for SWS quality. As GABA can inhibit brain signals and slow down nervous system activity, that could potentially mean that it will allow for processes that occur in light sleep (i.e. heart rate and breathing slows down, muscle relaxation, etc.) to occur faster.
Previous studies have shown that VTA dopaminergic neurons have been shown to increase wakefulness when activated. However, chemogenetic inhibition has the opposite effect where it can promote sleep behaviors even in the presence of survival stimuli (i.e. predator odor, appealing food, potential mate, etc.). By inhibiting these neurons, it can prevent sleep disruption and promote sleep.
On the other hand, glutamatergic neurons signal the brain to enter REM. During REM, the brain is at its most active state, where muscles are temporarily paralyzed. Glutamatergic neurons are responsible for inducing this temporary muscle paralysis that prevents you from hurting yourself during REM.
All Somna users will have a two-part experience: 1) a noninvasive surgery to insert genetically modified neuron receptors into sleep-regulatory neurons 2) consume nightly ionized water that will activate these receptors for higher quality sleep.
Noninvasive Surgery using ATAC
Acoustically Targeted Chemogenetics (ATAC) is a non-invasive chemogenetic delivery method that can be used for drug delivery and expressing specific neurons in the brain. There are 3 steps to this procedure:
- Inject viral vectors containing genetic information for receptors into the brain
- Temporarily open up the blood-brain barrier using focused ultrasound so viral vectors can reach their target locations
- Activate receptors using an orally consumed pharmaceutical
Adeno-Associated Viruses (AAVs) are small, single-stranded DNA viruses that can target and insert genetic material into neurons. Unlike most foreign invaders, AAVs are non-pathogenic to humans, meaning that even when inserted into the body, they won’t elicit an immune response. AAV vectors are replication-deficient, meaning that they can’t easily spread between cells like normal viruses. For Somna’s approach, they will contain the genetic information that encodes for our receptors.
However, just injecting them into the body won’t ensure that they reach our target neurons. As a result, focused ultrasound (FUS) will be used to temporarily open up the blood-brain barrier, which protects the brain by preventing toxins, pathogens, or other unwanted substances from entering. While helpful in most cases, this can be problematic for doctors and researchers who want to deliver therapeutics into the brain to treat brain disorders and cancers.
Before treatment, microbubbles will be injected into the user’s body to reduce the amount of energy needed for the treatment and to lower the risk of hurting biological tissue in nearby areas. Microbubbles are micrometer-sized gas bubbles that can compress and expand depending on the oscillations exerted by the ultrasound beam. When the bubbles bump against the blood-brain barrier, they can create a temporary opening for larger particles (such as AAV) to enter.
Once the AAVs are able to enter the brain, they find their target locations using cell-specific promoters. A promoter precedes a gene and basically controls expression depending on if the promoter is activated or not. Certain promoters within the body can only be activated by a specific cell type.
Once they reach our target neurons, they are able to inject their genetic material and create modified receptors that can respond to Somna’s ionized water.
These modified receptors are known as DREADDs, or Designer Receptors Exclusively Activated by Designer Drugs, which are genetically modified neuron receptors that are programmed to respond to a synthetic ligand. There are two types of DREADDs that will be used: Gq and Gi. Gq is used to activate expression while Gi is used for inhibition.
Since we are inhibiting the dopaminergic neurons, we would use Gi while for the GABAergic neurons, we would use Gq. Both types of receptors can be activated using CNO.
Somna Vitamin Water
Following the noninvasive surgery, consumers can purchase a pharmaceutical medication that will contain CNO. Before going to sleep, the user can drink the medication, which will activate the DREADDs that were inserted into the target neurons.
By doing so, it will induce sleep faster, cutting out external factors (i.e. stress, background noise, etc.) that interfere with sleep. Inhibiting VTA dopaminergic neurons will promote sleep-related behaviors and allow for faster sleep induction. Next, with controlled activation of PZ GABAergic and glutamatergic neurons, we may potentially extend the amount of time that is spent within NREM and REM. Whether that is able to lengthen the time by a significant margin to cut down the number of necessary sleep cycles will need to be investigated further.
Bridging the Technical Gap
As futuristic as this sounds, Somna’s sleep solution has the potential to become a reality within the next 5 years! However, there’s still a lot of research and testing that needs to be done first to ensure the safety and efficacy of this approach.
While chemogenetics has been done successfully in various animal models, it has never been done in humans. As a result, the technology will need to undergo a rigorous process in order to get FDA approval. Within Somna’s solution, the combination of these different components may lead to unforeseen side effects that could negatively impact the brain. Additionally, one problem that arises in sleep medications today is intolerance, meaning that after the patient has taken it for a period of time, it gradually becomes ineffective. Perhaps, the consistent activation of specific neurons will lead to a similar effect where it will no longer work for the consumer.
Since sleep is a complex phenomenon more research is needed to investigate the neurons and elements that are involved in regulating sleep. As our solution involves activation and inhibition of neurons, more studies that combine the use of chemogenetics, as well as the simultaneous manipulation of these neurons, will be needed to create the best sleep solution possible.
With Somna, we can live in a world where only 4 hours of sleep are necessary each night, providing more time for people to do the things that truly matter to them. From spending more time with your family to pursuing your passion project: What will you do with those extra four hours?
Extra resources to get you started on a sleep rabbit hole:
Disclaimer: Somna is a hypothetical moonshot company that we created as a project. All the technology and research we referenced are legit, but at the moment, Somna is still just a sweet dream.
If you got to the end of this article and are interested in learning more, don’t hesitate to click on our company website for more information and extra resources on the topic. For a quick overview of our company and solution, check out this one-pager.
We would like to express our gratitude to Jerzy Szablowski and Robbert Havekes for providing valuable feedback and advice on our project!
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