Announcing: Constellation Bio

A long time coming.

In 1747, a man named James Lind conducted an experiment that, these days, is widely recognized as the first randomized controlled trial.

Lind was a shipboard physician in the British navy, and had eight sailors with scurvy on his hands. He gave two of them vinegar, another two dilute sulfuric acid, two more got seawater, and the remaining two got citrus fruits. When the citrus group made a spectacular recovery, Lind knew he was on to something—so a few years later, when the famous captain James Cook was setting out on a voyage, Lind sent him off with a crate of lemon juice for his sailors, boiled and bottled to prevent spoilage on the long journey.

When Cook returned, he reported that Lind’s juice was bunk—no difference in scurvy rates between sailors who drank it and those who didn’t. Vitamin C, we now know, degrades when you boil it.

And so it was that the first-ever RCT was immediately followed by the first-ever failure to replicate exciting preliminary results, thanks to sloppy design when scaling up an RCT. It wasn’t ‘til 1779—more than thirty years after Lind’s original trial—that someone thought to try preserving the lemon juice with alcohol instead, and found that this maintained its scurvy-preventing magic.

I think a lot about that thirty-year gap. That lull, where the key discovery had been made—the cure for a horrible disease was this close to existing—but the implementation needed a little workshopping. How many men died grisly deaths, old scars turning into gaping wounds as their skin literally unraveled at a molecular level, all because Lind and Cook’s ill-fated test threw everyone off the scent? How many lives were lost for want of a technology that was, essentially, a pre-mixed margarita?

How many things like that are out there, right now? How many puzzles with life-and-death stakes could be solved, if someone would just pick up the pieces we have lying around and tinker with them a little?

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In the last decade or so, we’ve learned a lot about the gut microbiome. So far, all signs indicate that, if we can learn to manipulate it with enough finesse, it has the potential to revolutionize human health. When we gene-sequence the bacteria in a person’s poop, we find that—in practically every poorly-understood health condition—some common species are consistently missing, or others are present in excess.

So what do we make of the finding that lower abundance of Eisenbergiella in the gut is associated with worse seasonal allergies? Eisenbergiella is one of those bacteria we’ve had with us since the caveman days; maybe it’s important. Maybe it produces a natural antihistamine or something. Why is Fusicatenibacter saccharivorans depleted in a smattering of autoimmune diseases with weird names, like spondyloarthritis? Why is Ruminococcus gnavus some 30x more abundant in the guts of people with schizophrenia than in controls? (that one, I have ideas about; stay tuned.)

The skeptic’s refrain goes “Correlation is not necessarily causation”—but it’s a stone’s throw from there to nihilism; the sentiment that nothing ever happens and the world is not for us to understand. It’s possible—likely, even—that some of these relationships are causal: that a change to the microbiome is the driver of disease, and changing it back could set things right.

This is a hypothesis that, in theory, doesn’t have to be that hard to test. You find some people with allergies, you feed them some Eisenbergiella, you see if it helps. If not, hey, see if you can find some people with spondyloarthritis.

So why hasn’t it been done? Why are the drugstore shelves lined with dozens of probiotic brands, all of which contain the same old yogurt starter? Why are there a dozen companies selling microbiome tests that’ll helpfully inform you that you’ve got no Coprococcus in your gut—but zero companies that will actually sell you a Coprococcus probiotic?

Why, if all the research is so promising, does it seem like nobody’s actually doing anything with it?

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Well, for one thing: looking at the microbiome and doing something about it are two entirely different disciplines. The former, the computational side, is what’s boomed since ~2014, when gene sequencing got cheap enough that people could afford to poop into an Illumina for kicks. But actually growing the bacteria so you can feed them to people hasn’t gotten any easier since about the ‘80s. See, most of the “good guys” in your microbiome are strict anaerobes, which means it takes specialized equipment and an uncommon skillset to culture them. It’s not hard, per se, but it’s not something you can easily pick up without hands-on training by someone who knows what they’re doing.

So it’s a small field. In the US, there’s a handful of companies and a few dozen academic labs that have the equipment and know-how to culture the strict anaerobes of the human gut—the Faecalibacterium, the Bacteroides, etc. Sometimes, those university labs will get as far as running a rodent study on an interesting strain, but making the jump from there to a human trial is a massive undertaking; on top of the science itself, the admin and oversight required is a full-time job, so it’s not something you typically do without first winning a grant to fund it.

The private sector could have less red tape: A corporation isn’t beholden to IRBs and funding bodies the same way academia is—and since probiotics are regulated as a food in the US, developing a new strain could be as simple as bringing a new kind of cheese to market. But so far, most companies working on turning microbes into marketable products have tried to develop them as drugs. And the admin and oversight involved in that? That’s an entire company’s worth of full-time jobs. (Oh, and at the first hint of an underwhelming clinical trial, the whole thing implodes spectacularly and everyone loses those jobs.) “Ingredients” companies like Biose and Sacco—the guys that make the Bifido powder that goes into those zillion different whitelabeled brands—are starting to get their gears turning on the anaerobes problem, but they don’t typically run a large study until they’ve got a shelf-stable, market-ready product…which means putting in months or years of upfront R&D work before each attempt on goal.

Long story short: observational research is about ten times cheaper and easier than interventional research, so it progresses about ten times faster. As a result, there’s a huge gap: a lot of promising hypotheses that nobody’s gotten around to properly investigating yet, simply because there hasn’t been time—especially when scientists capable of doing so are few and far between.

But I am one such scientist, and so I’m starting a company to turn all this research into something real: to put these correlations to the test, as directly and efficiently as possible, find out which ones really are causal, and get those bacteria on the market and into the hands of people who need them.

My goal is to create something less like probiotics as they exist today and more like gene therapy. These will be precision products, designed to fulfill a specific ecological and biomolecular niche, rather than something vague like “support gut health”. They will not be freeze-dried powder in a pill. They will, with any luck, be one-and-done solutions: you take enough that the bacteria set up shop in your intestines, eating your food and reproducing, providing health benefits for months or years to come. This goal—engraftment, as it’s known—is considered by many to be the “holy grail” of microbiome science, but it’s not too high a bar; after all, this is how all the bugs already in your microbiome do it. (Really, it’s outrageous that the current probiotics paradigm has people renting their gut bacteria. In this age of everything-as-a-service, of “You’ll own nothing and like it,” don’t we deserve to at least own our living selves?)

I’m calling the company Constellation.

Tune in next time for why we’re calling it that. Image generated with the prompt “Garden of Earthly Delights Space Program”.

I’m raising money—if you’re a high-net-worth reader and you'd like to back me, reach out—but I’m not waiting for a round to close to get started. I’ve already got the lab up and running, and we’re in human testing on our first product. Naturally, I tried it first; it’s a strain isolated from my own microbiome, so that was the logical place to start the safety tests. But now we’re on to figuring out how much it takes to get engraftment in someone who’s missing it. We’ll talk more about the specifics of this project in the next piece, but if you want a sneak preview, check out Constellation Bio’s website and reread my old post High Cholesterol? There’s a Bug for That.

But I think this is important to highlight: we are skipping the in vitro cell culture models, we are skipping animal tox, we are skipping freeze-drying and the dozen other in-between steps that ostensibly move the ball downfield but, in the end, mostly serve to get grants, keep postdocs busy, and put off the day when you risk finding out that your hypothesis was wrong.

We are doing it quick and dirty, going straight into humans, taking shots on every goal in sight. We are doing it with rigor and urgency; with alacrity.

We are doing this because, while there are risks in taking any drastic action, risk is only the possibility of harm, and it amounts to nothing when weighed against the certainty of harm we face if we don’t act. How many people will have a stroke between now and when this cholesterol bacterium is ready?

Too many.

I’ve written before about the difference between opinions and convictions: An opinion is something that’s consistent with your worldview, that you’d say you believe if asked—but a conviction is something that you live by, that you really act like you believe. And while I see a lot of people talk about the microbiome holding the key to the future of health, I don’t see anyone acting with the urgency of someone who truly believes: We might be able to cure high cholesterol, the thing that is statistically the most likely to kill you and your loved ones. We might be able to rid people of depression, yank it out by the root, save them from the suffering that drives people to suicide. To lift the rock of anxiety off a friend’s chest, put the freshness back into the breeze on their skin. Against such urgency, multiplied by millions of souls struggling under those burdens—is any action too drastic?

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We know, from the story of scurvy and a dozen other stories like it, that dedicated scientific effort can vanquish horrible diseases. A skeptic might say the vitamin deficiencies were low-hanging fruit; that it’s easy when the cure is “eat an orange once in a while”. But a lot of our gut bacteria are like vitamins, in that the body expects to have them around, and has for so long that it’s not meant to function without them.

So this is my conviction: these bacteria are our birthright. They’re pieces of us. And it’s only through the vicissitudes of modern life—antibiotics, atomization, the industrialization of food—that we’ve begun to find ourselves without them.

What miracles are within reach, if we can manage to give people back the bits of themselves that they’ve lost?

We’re going to find out. Let’s get to work.