Recall, if you will, that elementary school classic, “Guess How Many Beans Are In The Jar.”
Over the years, I’ve guessed at many beans in many jars, but none sticks with me like the first: Halloween, 1998. I was dressed as the Mona Lisa. The jar was filled with jelly beans. I counted all the ones I could see on the bottom, then all the ones I could see on the sides, and I came up with a number that was somewhere around 150. Then I bumped it up a little bit for the beans I couldn’t see, by about another 100, and ended up at a number that was remarkably, phenomenally wrong— too low by a factor of five.
People underestimate volume! We look at what we can see on the surface and think “okay, so… a little bit more than that.” But that’s not how adding a dimension works. With each added dimension, you explode the space of the possible.
A four-inch-by-four-inch square that gets an extra dimension to become a cube goes from a surface area of 16 square inches to a volume of 64 cubic inches. Add the dimension of time to static images and you get all of television and cinema.
I say all this because a dimension that is sorely underestimated in medicine today is time. Chronomedicine—or circadian medicine, harnessing circadian rhythms to optimize treatments—won’t just introduce 5% boosts here and there to the efficacy of a subset of drugs. It will vastly expand how we think about drug trials, interpret results, and translate findings into clinical practice.
With half the genome rhythmic, it’s been estimated that nearly all drugs could be optimized in terms of timing in some way. (Not to mention, half of all drugs are metabolized by a single liver enzyme which is known to show circadian rhythms). And the timing effect sizes we’re talking about could exceed the effect size the drug was originally approved for.
I think timing in medicine has been underexploited for a couple reasons, but one big one is that its effects have been underestimated, the same way I underestimated the volume of a jar as an elementary schooler. There could be different timing strategies for different therapeutic targets of the same drug. Efficacy and toxicity trade-offs could be titrated with timing, the same way dose amount is tuned. Timing could breathe new life into failed assets or drugs coming off-patent. And because time is a whole additional dimension, the odds are pretty good that whatever I’m guessing at is an underestimate.
To be clear, I’m not bullish on chronomedicine because I’m extrapolating from jellybeans. I’m bullish because of the data I’ve seen, where timing makes the difference between recovery and death. I’m bullish because of the mechanistic understanding we’re now starting to have of what’s causing time of day effects under the hood, and how we can exploit them.
After my devastating failure in 1998, I came back to the same Halloween party the next year and crushed the bean counting game, winning a t-shirt as a record of my glorious triumph. (It says “I Got Spooked!” and lives on as one square in a quilt on my couch these days.) The secret was choosing a number bigger than I thought was possible and taking the leap— it had to feel too big to be right.
But I don’t feel like I’m taking that same leap of faith with chronomedicine: I already know the circadian revolution in medicine will be tremendous. The only question is: how much further than what I’m imagining will it go?
