THE young, dark-haired woman ran rapidly down the stairwell, grinning. The numbers worked. They worked!
It wasn’t a clinical trial, of course, with a control group and actual human beings. Only virtual, run through millions of iterations by Archipelago’s deep medical AI.
But so far, everything Asklepios had predicted to happen in the human body, had happened.
She stopped at the landing, unable to wait, and texted the head of her research team.
Asky confirms 80% effectiveness in gen pop, Dr. Nan Lenson texted. Might just have effective agent. On way down 2 u.
THE influenza ravaging first Asia and now Africa was a virus, of course. A subtype of a common avian flu. But viruses “drifted.” Shuffled the decks, reassorting segments promiscuously from other strains they encountered.
And once or twice a century, you got something devastating.
“Central Flower” had emerged in Asia two years before. No one knew from where, but it had picked up a deadly gene. The CDC infectious disease team in Vietnam had estimated a 40 percent mortality rate.
Vietnamese researchers had isolated the virus, named it, and forwarded samples. The new strain produced a protein that shut down the normal immune response. Combined with the privations of wartime—reduced nutrition, long work hours, and the psychosomatic distress of worry and fear—the result could be cataclysmic.
As Nan Lenson had told her father, Dan, months before, it might actually be good that the world was at war. The lack of travel seemed to have slowed its spread. But that barrier wouldn’t stop it long.
The world faced another pandemic. Like the Spanish Flu in 1918. The CDC alert level stood at Phase Six, the highest level of the disease alert system.
Glaxo and Merck had produced candidates for a monovalent live attenuated vaccine. Unfortunately, the Glaxo version hadn’t panned out, and the Merck vaccine generated higher than acceptable rates of Guillain-Barré Syndrome in older recipients.
A year before, Dr. Anton Lukajs, head of Archipelago’s research team, had assigned Nan to research a family of advanced antivirals. They inhibited the neuraminidase protein that locked into the healthy cell and let a virus inject its RNA. She’d used reverse genetics to investigate the interactions that made the virus so dangerous. When she’d characterized the segments, she found a unique carboxyl terminus. Mapping that structure out on the molecular level had eventually elucidated how it evaded immunity and hijacked healthy cells.
Nan had worked with Dr. Jack Jhingan, Asklepios’s acolyte, to model the interactions in the body, trying to find or create a compound to block that terminus. To throw a monkey wrench into how it reproduced inside the cell. Or, alternatively, make it visible again to the immune response, so it didn’t get inside at all.
Under Nan’s direction, they’d tested the antivirals on ferrets, one of the few animals other than humans susceptible to influenza, isolating the subjects in the Army Level Five containment site at Fort Detrick. But without much success, and she’d concluded that the animals weren’t really homologous to humans in their reactions or transmission rates.
Every approach had hit a dead end. And the virus continued to spread.
Then Asklepios had integrated a deep neural network that modeled and predicted large-molecule interactions with the body. And Nan had asked it a simple question. Simple to ask, but unimaginably complex in what it demanded of the program.
What would be the formulation of a molecule that would block the linking action of the carboxyl group of Central Flower’s neuraminidase protein, while demonstrating low toxicity, high activity, high solubility, and minimal risk to patients?
After twelve hours of dedicated thought, the AI had just delivered a hit.
DR. Lukajs was in his office. One wall, all glass, overlooked the central mall. Elms and maples were scattered across green lawns dotted with pergolas, pathways, and ponds large enough to pass for small lakes. The central mall was encircled by the immense blue-glass-and-metal ring of the Archipelago campus. Four stories, two square miles, of the most advanced science in the world.
“It’s derived from Cytoxan,” she told Lukajs, who stood with arms crossed, looking wearily skeptical as usual, before a screen. Biochemists seldom used test tubes these days. The discipline was as dependent on computers as every other science now.
The lead virologist was emaciated, with a wispy fringe of white hair and brown age speckles like spilled coffee dotting his hands. After barely surviving radical prostate surgery, he moved with the tentative fragility of the very old. He frequently smelled of urine. A living meme of the classic nerd, he wore a white lab coat with a pocket protector, a narrow black tie, black oxfords, and plastic-rimmed glasses. Lukajs was Albanian. He’d grown up under Communism, studied in Moscow, and hated working for private industry. “Criminal profiteers,” he called them. Archipelago he tolerated, since it was a congressionally chartered corporation, like the Red Cross or the NIH. In some ways he was a dinosaur. But still, he had a frighteningly acute intellect.
“Cyclophosphamide? Already I don’t like it.” He waggled fingers dismissively. “An alkylating nitrogen mustard antineoplastic. Activates in the liver to form aldophosphamide. Side effects: hair loss, sterility, birth defects, mutations, cancer! This is what you bring me to cure Chinese flu?”
She pushed her notebook into his hands. On its screen a colorful, immensely complicated molecule rotated slowly in a 3-D display. “It’s not cyclophosphamide. It’s an isoelectronic structural analog. I screened the database. It’s not in the literature.”
Grumbling, the lead virologist carried the computer to a slanted table, adjusted the screen, and studied it. The visual resembled an exploding star system seen by the Hubble telescope, with its color-coded strands of sugars, proteins, chains of atoms. He cleared his throat and leaned closer. Tapped the surface to stop the rotation. Then spread his fingers to zoom in on one branch of the molecule. “This is a transition state analog.”
“I believe so, Doctor.” Such an analog resembled the transition state of a substrate molecule in an enzyme-catalyzed chemical reaction. And the human cell responded to viral infection by releasing enzymes. “Of course, that’s just the initial candidate compound. We can modify it to improve recognition and binding geometries.”
He studied it for several more seconds in silence. “Hmm. Aah … I think I see … clever. The conventional approach, to sensitize the immune system to surface proteins. But this lets virus attach to the plasma membrane. Hemagglutinin to sialic acid.”
“But inhibits the cell’s response,” she pointed out.
Lukajs mused on, as if she hadn’t spoken. “The virion … attaches. Injects mRNA. Yes. But this inhibits the enzyme it uses to translate into protein. No enzyme activity, no protein, no genome replication.” He squinted. “But what happens to the RNA then? It is still inside, yes?”
Nan said, “The cell’s defenses destroy it and MHC class I pushes the debris out onto the cell surface.”
Lukajs milked his tie, grimacing. “The artificial mind says this, yes? So clever it is. But it doesn’t think, what happens next? Cytotoxic T tags cell as infected with a toxic mediator and kills it. So cell still dies, in the end.”
She nodded. “But no daughter viruses are replicated. Once the initial viral load’s exhausted, the infectious process ends.”
He glanced sharply at her. “Database search?”
“Came up empty.”
“Toxicity?”
“Worrying, but we could pretreat with amifostine. Reduce the hematologic damage, but still get the antiviral efficacy.” She caught his frown before he could object. “Or maybe not amifostine. Something like it, though. We could run virtual trials on pharmacophores. Like I said, to bump up the binding geometries. Hundreds of them. Or thousands! The system’s that fast.”
“It might be worth trying,” the old man said grudgingly. But she’d watched a light grow in his eyes as he examined the molecule. Grasped what the drug might be trying to do.
“I’ll start writing it up for Drug Discovery,” she said. Started to turn away. But found her arm seized.
“Just a minute, Dr. Lenson. No. You will not publish this.”
She looked down at his hand on her upper arm until he released it. “Sorry. A transgression of social norms,” he muttered.
“Don’t we want priority?”
“You don’t recall who are we working for here. A responsibility to—how do you say—the ‘customer.’” Lukajs wrinkled a bulbous nose.
Outside the window, a buffeting wind thrashed the trees. Leaves leapt up, whirling in the gusts. She crossed her arms. “I don’t understand your reluctance, Doctor. This may save many lives.”
But the elder scientist was shaking his head. “We need tests. Protocols. Clinical trials. Far too soon to publish. Who says it cannot be toxic? Word of computer? We will be laughy stocks.”
“Meanwhile, let people die?”
“Is not pandemic yet.”
“Maybe not here, Doctor. But millions are sick in Asia.”
“In Asia.” Lukajs gave a nearly imperceptible shrug.
But the next moment he held out a hand as if to take it back. “I did not mean. No. Far beyond social norms. What I meant—we will proceed. You will meet with pharmas. Produce test quantities. Plus any isomers. I will advise the board to set up trials. Alert BARDA we might have candidate for production.” The Biomedical Advanced Research and Development Authority contracted for drugs in public health emergencies. “But you are correct about the ferrets. Not useful subjects. Perhaps we can obtain access to better.”
Ferrets? For a moment she drew a blank. Then had a bad feeling. “Better subjects—what does that mean?”
“Perhaps, from the government. Volunteers only, of course.” The old man smiled, reached out to pat her, but paused his hand halfway. “When time comes, we will share credit. Is your discovery, yes?”
“Actually, it was Asklepios’s.” But a glow ignited at the thought. She was still only a junior researcher. After the war, funding would be far harder to come by than it was now. A success like this—again, assuming the mechanism of action worked as predicted—could make her career. Could let her pursue some of her own ideas, like inhibiting other enzymes. The ones that allowed cancerous cells to evade apoptosis, for example.
“So we are agreed?” Lukajs looked out the window, down at the tiny figures far below. At researchers strolling or tossing softballs, kicking soccer balls, taking a break from work. “We do this the right way. We will not jump the rifle. We will not post to journals. You work with the pharmas to produce. I will have Dr. Jhingan set up the trials. And when they are successful and we publish, you will both receive co-credit with me. We are agreed?”
He held out a hand, age-spotted, trembling slightly; and after a moment’s hesitation, she accepted it.