"Off-label?"
Rachel tilted her head curiously beside me, clearly unfamiliar with the term. But as someone with a medical background, I knew exactly what it meant. "Off-label" referred to the use of a drug for an unapproved purpose—not for the condition the FDA had originally authorized it to treat, but for something entirely different.
In other words…
"You believe there's already a treatment available," I said, catching on. David responded with a sly grin.
"Exactly. It's possible there's a drug on the market that we're just unaware of."
This was a possibility I hadn't considered at all.
'It's not impossible,' I thought.
Drugs aren't bespoke creations designed for a single purpose. A single treatment can address multiple conditions. Take sildenafil, for example.
Better known by its brand name Viagra, sildenafil received FDA approval in 1998 for treating erectile dysfunction.
But by the early 2000s, some doctors were using it to treat heart and lung conditions in infants. Its mechanism—dilating blood vessels—allowed it to be effective for pulmonary hypertension, even though it had only been approved for erectile dysfunction. While clinical trials for pulmonary hypertension were lengthy and delayed its approval for that indication, sildenafil finally received FDA approval in 2023 as a treatment for pediatric pulmonary hypertension.
"Off-label, huh…" I murmured. Just as Viagra treated pulmonary hypertension, there might already be a drug out there capable of treating Castleman disease. According to David, all we needed to do was find it.
"There's a possibility, but why are you so confident about this?" I asked.
"This might take a while to explain…" David began. He launched into his hypothesis, which boiled down to this:
Castleman disease involves a "malfunctioning switch" in the immune system. The only defective switch conclusively identified by researchers so far is Interleukin-6 (IL-6). Interleukins are a type of cytokine secreted by cells to facilitate communication between them.
"But according to the latest clinical trials, a full two-thirds of patients don't respond to IL-6-targeted treatments," David said.
"What if, for those patients, the problem doesn't lie in IL-6 or even the cytokine pathways? What if there's an entirely different mechanism at play?"
David's argument was simple: There isn't just one defective switch; there are multiple switches, and the remaining ones might function completely differently from IL-6.
"Current research focuses exclusively on interleukin and cytokine pathways, even though 66% of patients see no benefit. That's why progress has stalled. If we expand the search to encompass the entire immune system, we'll likely find a drug that works."
As someone from the future, I knew David's hypothesis was correct. The critical question was the identity of the remaining switches.
"If you're suggesting we examine the entire immune system, the scope is too vast. Which pathways should we target specifically?" I asked.
"That's why we should try off-label drugs," David replied.
"What?"
"We need to narrow down the candidates," he clarified.
66%. 33%. I found myself swallowing dryly. This approach was absurd.
"You're suggesting we work backward?" I asked.
"Precisely."
'He's insane.'
Typically, drug development begins with theory and progresses to clinical trials: identify the cause first, then develop a treatment. David wanted to flip that approach.
He was proposing we start by testing all existing immune-related drugs on the market, one by one. The odds of finding a match? Slim, but possible.
It was reckless. No, reckless didn't even begin to describe it.
But…
"If we want to find a treatment within the next ten years, this is our only option," David declared.
And in the end, he was right. Using this method, David discovered the second treatment for Castleman disease.
So, it's best to hear the details first.
"It makes sense, but the list of candidates seems overwhelming."
The FDA has approved hundreds of immune-system-related drugs. Testing each one would make finding an answer within ten years impossible.
"Of course, I'm not planning to try them randomly. I've formed hypotheses and narrowed down the most promising candidates…"
"Can I see the list?" I interrupted.
"Here," David said, handing over the list. At the very top, a line was prominently drawn through the first entry. I immediately recognized its significance.
"You've already tried it yourself."
David flinched, then broke into laughter.
"Haha! You caught that, did you? Yes, I became my own guinea pig!"
Of course, I knew. When I was nearing death, I wanted to try anything, even begged my doctor for experimental drugs. But I was told none existed. Powerless, I could only wither away.
David, however, is different. Even after enduring four seizures, he is healthy enough to scour for drugs and recklessly test them on himself.
"As you guessed, I started with number one: cyclosporine. While it didn't improve my symptoms, the seizures didn't worsen for three days."
Cyclosporine is an immunosuppressant that prevents organ transplant rejection. Using it slowed the rapid multiplication of defective cells but didn't completely halt the process.
"Perhaps suppressing T-cell activation caused this. If so, it might mean T-cells play a crucial role in the initial seizure phase."
He doesn't yet understand what this symptom means, but accumulating more data will eventually provide answers.
"I'll try number one again, and if I see similar results, I'll move on to number two."
"What side effects do you expect?"
"I have no idea. I'm just hoping they're not fatal."
I returned my gaze to the list.
Excessive T-cell activation: Cyclosporine
Overexpression of VEGF: Bevacizumab (approved in 2004 for colorectal cancer)
MTOR pathway issues: Rapamycin (approved in 1999 as an immunosuppressant)
In total, there were fifteen defective switch candidates. The list seemed scientific, derived from theory, but the method itself was perilously dangerous.
Testing drugs for unapproved uses means no one can predict the side effects. It could lead to gastrointestinal bleeding, brain hemorrhaging, or a heart attack. Even if he survives the side effects, repeated trials will almost certainly damage his liver or kidneys.
He might die from something unrelated to Castleman disease.
The cure has to be found before that happens.
"This is Russian Roulette," I muttered.
"An apt metaphor," David replied. "I'm spinning the chamber because, either way, I'm going to die."
This isn't medicine or science. It's gambling. Pulling the trigger while unsure whether you'll live or die.
"With this approach, you'll need more than an individual—you'll need a group," I pointed out.
"…Yes," David admitted.
Playing Russian Roulette alone is meaningless. With just one participant, the chances of dying from side effects outweigh the chance of discovering a cure. A group is necessary.
If one person dies, the next must pick up the revolver. They must all pull the trigger, one by one, until the cure is found.
"…"
I frowned. No matter how unrestrained a country might be when it comes to ethics and morality, this felt extreme.
This isn't about gambling your own life. It's about gambling with the lives of others.
It means standing before countless people pulling the trigger and stepping over their bodies to reach the cure.
"You'll die, but sacrifice yourself for the sake of others… Not many patients would agree to that."
"Not necessarily."
David cut me off firmly, his resolute gaze locking onto mine. His unyielding eyes were unwavering.
"The patient community is actively seeking this," he stated.
"As I mentioned, IL-6 inhibitors don't work for 66% of patients. I'm one of them."
His gaze slowly dropped to the floor, where it stayed fixed.
Without a hint of emotion, he continued.
"Patients see things differently. Doctors only offer one treatment. The chance of that treatment working is 33%. For those outside that percentage, it's effectively a death sentence. You write your will in advance and wait for the next seizure in a hospital bed. A life where death is certain, but the reason for it remains unknown…"
David spoke calmly, conveying the despair of patients in a flat tone, his expression unreadable. It was the demeanor of someone long accustomed to hopelessness.
"For such patients, Russian Roulette isn't just a gamble. It's their final chance to fight for survival."
This wasn't about sacrificing oneself for others. For these patients, the Roulette was their only hope. That's what he was saying.
'Right… That's how it is, isn't it?'
Caught up in the madness of this gamble, I had momentarily forgotten the perspective of the patients themselves.
I, too, had sought out a roulette in my final moments. If someone had handed me this revolver back then, I would've pulled the trigger without hesitation—even if death was the outcome. Dying while doing nothing, or at least taking a chance on my own terms—those were completely different.
The deprivation of even that slim opportunity was a pain as unbearable as the illness itself.
Patients on the brink of death crave Russian Roulette—desperately so.
'What should I do…?'
It was time to make a decision. I tapped my thigh lightly with my fingers, organizing my thoughts.
'This wasn't part of the original plan.'
I had intended to follow a traditional path: theorize in a lab and develop a drug based on that theory. The reason I sought out David was that he had discovered the second treatment.
Until now, I believed he was a brilliant researcher—someone who made breakthroughs in the safety of a lab, meticulously studying the disease. I thought funding such a genius might lead to a third treatment.
I was wrong.
David isn't a genius researcher. He's a gambler.
His method is Russian Roulette. Even David doesn't know the right answer. You only find out when you pull the trigger.
Research or gamble?
'If I compare success rates…'
Even ten years later, the cause of Castleman disease hadn't been discovered—at least not in a lab. Meanwhile, Russian Roulette had already produced a second treatment. That treatment hadn't worked for me, but if the Roulette kept spinning, a third treatment could emerge.
In terms of potential success, Russian Roulette had the edge.
But…
'The risks are exponentially higher.'
Russian Roulette extracts answers by grinding through countless lives. In a sense, it's no different from human experimentation. The backlash would be immense.
David would be branded a murderer gambling with patient lives. I'd be labeled an investor funding murder with $50 billion.
It's dangerous.
But every investor knows one fundamental truth: there is no such thing as a safe path.
If risks are well-managed, they become opportunities.
High risk, high reward.
I had made my decision.
"I'll join this Roulette."
"What?"
David's eyes widened in shock. He had expected me to consider it but clearly hadn't imagined I'd actually say yes.
"I'll cover all the costs for this Russian Roulette."
It wouldn't be cheap. But I had already budgeted for up to $50 billion. Still, I wasn't about to hand over that money without strings attached.
"However, there are conditions."