Last shot

Chapter 15

Dolan cracked his knuckles for the third time that morning, psyching himself up for the confrontation he'd been rehearsing in his head since he woke up. A glance around the lab and his anxiety gave way momentarily to pride at all his work had given rise to.

He'd stumbled into the field, awed by the progress made by those scientist-pioneers who'd come before him. They'd made a brilliant leap. An imaginative leap. Brilliant and imaginative the way that Darwin's mechanism for evolution had been-simple and sound. Once you got it, it was all but obvious. All the pieces had been there; it was just a matter of assembling them to form the right picture. And unlike natural selection, viral vectors could be tested over weeks, not eons.

Gene therapy arose to correct genetic disorders that were deemed incurable. The bench work, while complex, was straightforward. Take a virus, designed through natural selection to penetrate human tissue, and excise the DNA sequences that make it virulent. Once it's been defanged and declawed, what remains is a biological vehicle with plenty of cargo room-a microscopic Trojan horse. Insert a therapeutic gene and the formerly threatening virus acts as benign transport. Once the viral vector is introduced into a subject, it finds its way to the target DNA sequence on the appropriate chromosome and the transgene insinuates itself, replacing the faulty gene.

Dolan had always been taken not just with the medical ramifications of viral vectors but with the elegance of the mechanics. And over the past few years, under the auspices of his own Vector Biogenics, he'd made not one but two breakthrough contributions to the field. They had come in relation to alpha-1 antitrypsin deficiency, an obvious disorder to tackle, since all its complications arise from a single set of faulty genes. Other grails were out there, sure, cystic fibrosis, maybe even familial hypercholesterolemia after that, but for now his (and Vector's) hopes hung on perfecting a viral vector that could deliver a gene to correct AAT deficiency. A dire disorder, usually diagnosed in childhood. Instead of producing a protein that helps coat and protect the lungs, the liver of an afflicted patient generates an abnormal enzyme that accumulates inside the liver and eventually shuts it down.

Dolan had chosen lentivirus and smallpox for his development models because they were nice roomy viruses, Mack trucks to the Mini Cooper of the more experimentally plumbed adenovirus. His first landmark vector-and still his pet project-had been born in relatively short order.

Lentidra.

The lentivirus vector (the latest model was code-named L12-AAT) had been his favorite from the gates because it seemed consistently to provide permanent integration of the transgene into the genome-one shot and the subject was cured. Optimistic from all theoretical indications, he'd handed over his creation to the study director who would conduct animal trials. But Lentidra's preclinical studies were abruptly suspended, after initial reports had come back riddled with problems. After this first, failed model, Dolan had to set his sights lower, temporarily relinquishing the dream of long-term gene expression and, at the board's urging, turning his focus to his redheaded stepchild, the smallpox vector (now known as X5-AAT and by its more marketable title, Xedral).

Rather than integrating into the host's genome, Xedral allowed only for short-term gene expression; the DNA floated in the nuclei of the target cells, got expressed briefly, then faded. The treatment was effective-86 percent effective from trial indications-but not a cure, and it required a booster shot once a month for maintenance. Otherwise the subject would slide back into his failing condition. In animal studies, Xedral was looking to be safer than Lentidra and more effective. These trials showed a stability of transgene expression sufficient to bring Vector to the verge of FDA Phase I human studies. A number of volunteers, mostly children, would begin trials within the month.

Dolan still mourned the loss of Lentidra. The idea of cure was tantalizing. Next to prevention, it was the best thing a medical scientist could deliver.

In fact, the notion of long-term transgene expression was what had sparked Dolan's interest in the field. When, while coasting through UCLA as a biochemistry major, he'd first learned of the huge advances scientists were making using viruses to shuttle genes, he'd been possessed intellectually. Casting aside a (lukewarm) aspiration for medical school, he'd dived into research, fretting over mitochondrial-derived activators for a promising but uninspired senior thesis. He'd stayed in the department for a Ph. D., blissfully engaged in his research. He loved playing detective, tugging at analytical knots, plank-walking out to areas of specialization where he alone could generate answers to the questions he was posing. And, better yet, he was gifted at it, his dissertation work knocking the experimental frontier forward a longitude or two.

Dolan's thoughts returned to the concern at hand, and he leaned forward, resting his elbows on his workstation. For all its sloppiness, his bench was organized precisely to his liking. It was the one place he felt at home. His machine-sharpened Faber-Castell number-twos, his DNA samples, his microfuge tubes.

When he strayed beyond his bench, however, the particulars of ownership became a bit hazier. Beacon-Kagan, the pharmaceutical behemoth that was Vector's parent company, brought its influence to bear in imaginative and indirect fashion. Ostensibly, Vector had its own management, but it was a wholly owned subsidiary with plenty of Beacon-Kagan executives on loan and more cross-board memberships than would have been orthodox a few presidential administrations ago. In return for these unnegotiated concessions, Dolan, as the principal investigator and senior scientist, enjoyed a relative freedom from budgets and business concerns. He mostly kept to his domain, what others called research but he always called science, constructing his viral vectors in his sheltered corner of the lab.

Having assumed the lease at the board's insistence from a failing digital-TV company, Vector occupied the ground floor of the twenty-six-story Beacon-Kagan building in Westwood, located just below UCLA on Wilshire. In his private moments, which were many at work and few at home, Dolan likened Beacon-Kagan to a twenty-five-story ogre perched on his shoulders. But what a rich infrastructure for Vector to flourish in. And flourish it had-thanks to Xedral-to the brink of a closely watched IPO. Watched from the Street and from above.

Dolan pivoted now in his barstool-height architect's chair, working up the nerve to confront the board's pet study director (in title at least, Dolan's employee) about the aborted Lentidra trials. Casting nervous glances across the lab through the two glass walls into the test-subject suite, he waited for Huang's head of shiny black hair to appear. It was early-6:00 A.M. early. Any Beacon-Kagan employees (and that meant any Vector employees) who didn't want to wither in the corporate culture started their days before their days.

Huang finally swept into view, wearing his knapsack, an accessory-like the Trek twenty-one-speed he "commuted" on-that Dolan had always thought an affectation of youthfulness. Dumping the knapsack onto his desk, Huang tugged his lab coat from his chair back and slipped into it, completing his transformation into authority figure. Sipping a Starbucks, he pulled himself to his monitor.

Dolan stood, trying to override unease with indignation. Why shouldn't he confront Huang? After all, wasn't it Dolan's company? Vector Biogenics wouldn't exist were it not for him. As the father of the process and the senior scientist, wasn't he entitled to a few simple information requests?

He started for the door, muttering to himself, drawing curious gazes from the junior researchers. His resentment flared, putting an uncharacteristic conviction into his step. He gowned up and passed into the baking heat of the production room, a massive incubator where thousands of bottles rotated slowly on racks lining the walls. Made of polypropylene, a plastic on which cells readily grow, the roller bottles were filled with a red medium liquid. This growth fluid created a wet environment for the genetically altered smallpox to reproduce. In the batch currently spinning all around Dolan like living wallpaper, a mere three days into production, the virus had already swollen the cells and begun to bud out of them. A few more days and the production team could pour out the infected liquid and filter it. Once the Xedral was purified, it could be formulated, dispensed into vials, and freeze-dried, just like a standard vaccine. After that, just add purified water and inject.

Dolan stepped into the airlock, then out into the test suite, the monkeys grunting and banging their cages in greeting. With relative ease, Dolan had designed a viral vector to "knock out" the AAT gene, so that Huang could create an animal test group that simulated humans with alpha-1 antitrypsin deficiency (destroying-especially when it came to genetics-was always easier than repairing). Rabbits, mice, pigs, and woodchucks had all come and gone before Huang hit upon cynomolgus macaque monkeys, whose clinical presentation of the deficiency was sufficiently comparable to that of humans to make them useful in determining the effectiveness of Lentidra and Xedral. Simple intravascular injections, like flu shots, were administered, and thirty-six hours later the test monkeys no longer had functioning AAT genes. Their livers started to shut down; they lost weight; their sclera yellowed. Dolan had created the problem to fix it. And fix it he had.

How permanently his viral vectors could keep that fix in place was another question. The recovery of the monkeys had been staggering to witness. An added advantage in using higher animals was that the trials could continue longer; it wasn't until the eighth month of L12-AAT's second trial that Huang had caught the complications that had made the board pull Lentidra from development.

Dolan arrived at Huang's side, but the study director continued tapping at the keyboard, the monitor's glow reflected back in his glasses. "Just a sec, D."

Waiting, Dolan offered a salute to Grizabella, and she bared her teeth kindly and returned the gesture. One of 128 composing the final longitudinal Xedral study, Grizabella was the gentlest and (on those rare occasions when Dolan ventured into the test-subject suite) his favorite. Huang had started with 130 macaques but lost two to simian hemorrhagic fever, which was common enough in monkeys imported from the Philippines and, thankfully, harmless to humans.

Huang sent an e-mail with a flourish of his hand and spun on his chair to face Dolan. He flashed a boyish grin. "Herr Direktor."

"Chris, I took a spin through the preclinical reports you got me from the last Lentidra trial. I'm still having trouble reconciling the figures with the results. I'd like to take a look at the raw data."

"Again? We've gone around on this a few times now."

"And every time I found inconsistencies in what you submitted to me. I'd like all the raw data so I can rerun them myself. Top to bottom."

Huang blew out his cheeks. "Well, we're focused on Xedral now, right? We've got a functional model, and we're readying to hit market."

"Xedral's more or less autopiloting to Phase Is next week." Dolan set his fists on his hips, Superman style. "My work there is done."

"So don't we need you to move on? Lentidra didn't pan out."

"Exactly. But, you see, everything I oversaw on Lentidra did bear results-"

"In a petri dish."

"Which is why I want every piece of data since my vector crawled out of my petri dish and into your monkeys."

Huang laughed. "Fair enough. It's a ton, though. I'll need some time to pull it together."

"What's the challenge? Attach it to an e-mail and click 'send.'"

Huang jigged the chair back and forth so it gave off little squeaks. "Look, the board's been clear where we need to be putting our focus. Don't you think-"

"The board doesn't want to burn resources chasing a failed model for the sake of the senior scientist's ego. I get it."

A tension-releasing laugh. "You said it, not me."

"But you've got to remember, this company's based on vision, not just corporate expediency. The upside to Lentidra-permanent transgene integration-is huge. It's worth devoting a small percentage of our resources to backtracking and troubleshooting. I hate to sound like a commercial, but if I get a handle on the problem, I think I could engineer an alternate Lentidra design that would offer us the best of both worlds-the stability and safeness of Xedral with long-term genetic expression. If we nail it, who knows what the other applications will be?"

"Okay. I'm with you. I'll help. But we're all working late. And early." A gesture at the computer-screen clock. "We've still got limited time, and time-as our CEO is so good to remind me in our now daily meetings-is our most valuable capital. Based on what I'm getting from upstairs, obsolete vectors are not where our aim is right now. Our aim is the IPO. As soon as we get through the next few weeks, I'll dig out all the old data. Then we'll start breaking it down together in our copious spare time." Huang offered a hand and a smile. "Deal?"

Dolan did a quick translation: In his zeal to serve the board, Huang had put all his focus into Xedral, leaving the other data in sloppy condition. Though Dolan couldn't relate to Huang's lack of curiosity, he'd found it all too common in corporate researchers.

Dolan returned the handshake but not the grin. When he turned, Grizabella extended her hand through the bars and slapped him a solemn five. He passed through the automated glass sliding doors into the hall, Dean Kagan's pious oil portrait beaming down at him.