You think you've explored medicine. In reality, you're standing in the parking lot of Disney World bragging about how fun
the pavement is. You've taken pictures of the asphalt. You've written dissertations about the parking stripes.
You've never gone inside. After a century of pharmacology, most beneficial effects of molecules on diseases remain unexplored.
Not because biology is constrained. Because clinical trials are slow, expensive, and run by people who think "urgency" is
a type of perfume. Here's the math. It's painful but brief, like a flu shot administered by someone who hates you.
Your Tiny Sandbox. There are twenty thousand prescription products approved in the U.S.
It sounds impressive until you realize most are just "Tylenol, but blue."
These products contain only one thousand six hundred and fifty unique compounds.
That is fewer ingredients than a decent French bakery uses.
Seven thousand five hundred investigational compounds have passed Phase One globally.
Progress! The F.D.A. GRAS list contains six hundred and thirty-five substances.
These are things you could eat right now without dying. Low bar.
Still useful. Total unique compounds humanity knows are safe-ish: nine thousand five hundred compounds.
That's it. That's your entire medicine cabinet after five millennia.
The Target List (Ways Your Body Breaks). The I.C.D. ten lists fourteen thousand codes for ways your meat can malfunction.
It is humanity's most comprehensive to-do list, and you're ignoring it.
After consolidation, there are one thousand trial-relevant diseases worth actually fixing.
The Math You're Ignoring. Take your nine thousand five hundred safe compounds.
Multiply by one thousand diseases. This gives you the "Combinatorial Space," which is fancy talk for "stuff you could test
tomorrow if you weren't busy filling out forms." Nine thousand five hundred compounds times one thousand diseases equals
nine million five hundred thousand plausible drug-condition combinations.
What You've Actually Tested. There are one thousand seven hundred and fifty unique approved drug-disease pairings.
That is your entire medical canon. Thirty percent of drugs gain at least one new indication after initial approval.
The rest never get a second date. Let's be generous and say you tested ten times as many things that failed.
(You did. You learned nothing from them.) Total tested: thirty-two thousand five hundred relationships.
The Scorecard. Thirty-two thousand five hundred relationships tested out of nine million five hundred thousand possibilities
equals zero point three four two percent. Humanity has explored less than one percent of the theoretically testable drug-disease
space. You are the detective who searched one drawer and declared the case cold.
It's like reading the first page of War and Peace and writing a book report called "It's About a Party."
Technically accurate. Cosmically insufficient. Is The Untested Stuff Useful?
You might argue, "Maybe the other 99 percent is useless!". Biology would like a word.
Undrugged Targets. Mapping three hundred and fifty thousand plus clinical trials showed that only twelve percent of the
human interactome has ever been targeted by drugs. You're ignoring eighty-eight percent of your own biology.
It's like having a one hundred-room mansion and living exclusively in the bathroom.
Polypharmacology. Drugs are messy. They hit multiple targets.
F.D.A.-approved drugs often bind to things you didn't intend.
This means "side effects" are frequently "cures for something else" that nobody bothered to notice.
Every headache pill might cure Alzheimer's. You won't know until you check.
You're not checking. Network Overlap. Diseases cluster on shared biological networks.
Arthritis and Alzheimer's share biological pathways. The cure for your grandmother's dementia might be sitting in your grandfather's
medicine cabinet. But you'll never find out, because testing it would require paperwork that takes longer than Grandma has
left. The Universe is Big. You Are Small. So far we only counted molecules humanity already has.
The stuff in your cupboards. If you look at what's chemically possible, it gets embarrassing.
Chemical Space. Estimated ten to the twenty-third to ten to the sixtieth power drug-like molecules.
That's more candidates than there are atoms in your body. Or stars in the galaxy.
Or excuses from your regulatory agencies. Virtual Libraries.
ZINC twenty-two contains tens of billions of purchasable virtual molecules.
You could order them online. You haven't. Synthesized. You have made less than ten to the negative fortieth power of possible
molecules. Tested divided by possible is approximately ten to the negative twentieth to ten to the negative fiftieth power.
Effectively zero. You haven't even started. This is like exploring Earth by looking at one grain of sand on one beach in
New Jersey, then declaring you've "seen the world." You haven't.
You've seen a grain of sand. In New Jersey. Why You Are Still Sick.
It's not because science is hard. It's because you've built a system that is allergic to answers.
Trials Cost Too Much. A typical Phase Two to Three randomized controlled trial, or R.C.T., costs thirty to one hundred million
dollars (Median cost per patient forty-one thousand dollars).
At that price, you only test "sure things." Safe bets. Boring bets.
Bets that don't cure cancer. Clinical trials are a velvet-rope nightclub where the bouncer is a regulatory agency and the
cover charge is a hundred million dollars. Herd Mentality. Trials overwhelmingly test the same few biological targets due
to preferential attachment dynamics. Everyone studies what everyone else studies because that's how you get grants.
It's like if every explorer only went to France because France already had good reviews on TripAdvisor.
Meanwhile, undiscovered continents full of cures sit there, undiscovered.
No Profit: Most molecules have no patent. No patent equals no one hundred million dollar trial which equals no approval.
The cure for cancer might be aspirin plus vitamin D. Nobody will ever test it because you can't patent aspirin plus vitamin
D. The molecule that saves your life has to make money first.
If it can't, it won't. You die. Quarterly earnings go up. Neglect: If you have a rare disease with no market, you don't
get a drug. Your cells malfunction in an unprofitable way. The invisible hand of the market has weighed your life against
quarterly earnings and found you wanting. Sorry about your death.
It was a business decision. How Long to Explore Everything?
At the current pace of three thousand three hundred trials per year, how long would it take to systematically test therapeutic
possibilities? Tier 1: Single Compounds (Most Conservative).
Testing every known safe compound against every major disease: Nine point five million combinations divided by three thousand
three hundred trials per year equals two thousand eight hundred and eighty years.
That's almost three thousand years to explore compounds we already know are safe.
By that math, we won't finish until the year five thousand.
Tier 2: Combination Therapies (Still Defensible). Modern medicine increasingly relies on multi-drug cocktails.
Oncology, H.I.V., cardiology, psychiatry: all routinely use drug combinations.
So the real question isn't "does this one drug work?" It's "which combinations work?"
Testing pairwise combinations of safe compounds: Forty-five point one billion combinations divided by three thousand three
hundred trials per year equals thirteen point seven million years.
That's longer than Homo sapiens has existed as a species. And that's using only compounds with established safety data,
testing only pairs. Not triplets. God help you if you want to try triplets.
Tier 3: The Full Chemical Universe (Illustrative). Beyond known compounds lies the chemical space of ten to the twenty-third
power to ten to the sixtieth power drug-like molecules. At current trial capacity, exploring even the synthesizable fraction
would take longer than the universe has existed. The universe is thirteen point eight billion years old.
You need more time than that. To test pills. Pills that already exist.
We haven't even started. "But Won't We Run Out of Easy Discoveries?".
Some will argue "diminishing returns": the more we search, the harder each new discovery becomes.
This assumes we've already picked the low-hanging fruit. We haven't picked any fruit.
We're still in the parking lot arguing about whether fruit exists.
Diminishing returns only kicks in after you've explored a significant fraction of the space.
At less than one percent explored, every trial teaches you something new about human biology, improving your ability to
predict what works next. Learning compounds. Depletion is negligible.
You are nowhere near the bottom of the barrel because you have not yet located the barrel.
The math: even with weak learning, diminishing returns only matters after exploring roughly thirty-seven percent of therapeutic
space. For combination therapies, that crossover is roughly seven million years away at current pace.
You cannot have diminishing returns when you've barely started looking.
See the formal analysis for the equations. The Fix. The Oxford RECOVERY Trial (COVID nineteen) proved that large-scale pragmatic
trials can run for approximately five hundred dollars and deliver results in less than one hundred days.
Five hundred dollars versus forty-one thousand dollars. Read those numbers again.
One of them is the reason people are dying. With a decentralized framework for drug assessment, trial capacity increases
by twelve point three times: Nine point five million combinations divided by forty thousand seven hundred trials per year
equals two hundred thirty-four years. Still a long time, but at least it's a number with fewer digits than a phone book.
And the first few decades would capture the highest-value discoveries (the low-hanging fruit that current trial scarcity
forces you to ignore while people die in the waiting room).
More importantly, D.F.D.A. (a decentralized F.D.A.) builds permanent infrastructure for systematic therapeutic exploration.
The goal isn't to "finish." It's to stop leaving cures on the table while you form subcommittees to discuss whether to form
committees to review the proposal to consider them. The Bottom Line.
Humanity has empirically tested less than one percent of the drug-disease relationships that can be tested using existing
safe compounds. If you include the larger chemical universe, humanity has explored roughly one-quadrillionth to one-quintillionth
of what is possible. There are numbers so small that mathematicians get depressed looking at them.
These are those numbers. The overwhelming majority of therapeutic potential remains untouched.
Not because cures are impossible. Because trials are too expensive and too slow.
A decentralized, automated pragmatic trial system is the only route to systematically explore the remaining ninety-nine
point nine nine nine percent of medical space. You're not in the parking lot because there's nothing inside Disney World.
You're in the parking lot because the entrance fee is one hundred million dollars and requires seventeen years of paperwork.
People are dying in the parking lot. The rides are right there.
You can hear the screaming. (Fun screaming. Cure screaming.).
The cures are inside. Open the gate.