Hibernation is a strategy used by many animals to get through lean periods, such as winter. It conserves energy, and then gets back into action when the environment becomes more welcoming. Our species doesn’t need it much, since we’ve shaped our habitat to make it hospitable 365 days a year. But it could be useful in other ways: for example, to put the body on hold when every minute counts, such as in the event of an accident or illness. And a new discovery by researchers at Harvard’s Wyss Institute for Biologically Inspired Engineering brings us one step closer to that goal: an Alzheimer’s drug that appears to be able to push smooth xenopus tadpoles into hibernation (Xenopus laevis), a species of African aquatic frog that does not naturally enter a similar state of torpor.
The drug in question is Donepezil, and it is routinely used to combat the early symptoms of Alzheimer’s. Precisely because it has already been approved for human use, and therefore deemed safe enough at least in patients with Alzheimer’s disease, the drug is particularly interesting. “Cooling patients’ bodies to slow down their metabolic processes has long been done in medicine, to address wounds and the long-term consequences of serious illnesses, but at the moment it can only be done in a hospital setting,” explains Michael Super, an immunologist at Harvard who participated in the study. “Achieving something similar with a drug as easy to administer as Donepezil could help save millions more lives every year.”
Of course, for such a drug to be useful it must not only produce a state of torpor, but also allow the organism to emerge from it unharmed. And a drug previously studied by the same researchers, known by the acronym SNC80, had failed in precisely this respect: it induces a state of hibernation in smooth xenopus tadpoles, but causes severe epileptic seizures in humans.
To search for a molecule with a similar mechanism of action, but burdened by less dramatic side effects, the researchers relied on artificial intelligence, which allowed them to analyze over 370 compounds with a mechanism of action comparable to that of SNC80, until they found the most similar: Donepezil, a molecule known, in fact, because in case of overdose it can slow the heart rate and induce a state of lethargy in patients.
However, when used in its traditional form, Donepezil proved too dangerous, because after a few hours of administration, the torpor induced in the tadpoles was irreversible. The researchers then tried to administer it by trapping the molecule inside a nano-emulsion, and thus managed to make it much less harmful, and equally effective: the new formulation allows to keep the tadpoles in a state of torpor for a very long time, slowing down their mobility, heartbeat and oxygen consumption, with effects that are completely reversible at the end of the administration.
It is, of course, too early to think about seeing the drug used on humans. Rigorous safety and efficacy tests will be needed, and if these are successful, further research will be needed to establish the most correct dosage and the best route of administration. If it were to pass all these tests, however, such a drug could prove very useful in many emergency settings, such as in ambulances, where it could be administered to patients to slow their metabolism and minimize the damage suffered during transport to the hospital.