Knockout Mouse (18 page)

As I turned the corner, the first thing that caught my eye was a woman running for her car. At the same instant, I saw Gregory near the building entrance, speaking frantically into his cell phone. The woman was about five foot six, with straight brown hair that fell to her neck. She had to be Karen.

I followed Gregory’s line of sight and my blood ran cold. A maroon sedan was speeding into the lot. Karen reached a white
Honda and dug for her keys in her bag. The sedan screeched around the corner. I raced across the asphalt, entirely underestimating the car’s speed. The next thing I heard was the shriek of tires. The sedan was in a skid and coming right at me. At least Pratt, or his partner, had been nice enough to hit the brakes.

I dove out of the way and rolled into a gap between two cars, still one space over from Karen. Propelling myself under the car, I scraped along the pavement. Tires squealed behind me. I popped out on the other side and knocked on Karen’s passenger window. She gaped at me, terrified, from behind the wheel.

“I’m a friend of Sheila’s!” I shouted over the scream of the fire alarm. The maroon car had blocked Karen’s exit. I motioned for her to get out. “come with me!”

Either I had an honest face or she made a quick calculation between the lesser of two evils. Karen sprang from her car. We dashed in parallel rows away from the sedan. “Sheila was a friend of mine,” I repeated, yelling across the space between us. “I’ve got a Scout over here.”

We slowed in the lane between parked cars. The fire bell ceased abruptly, leaving us in a gaping silence. Karen kept her distance, eyeing the line of trees at the end of the lot and the boulevard beyond it.

A car door slammed. The head of Pratt’s partner bobbed among the glittering cartops.

“They’ll catch you if you run,” I warned. “They were hired by Dugan at LifeScience.”

That did the trick. Without saying a word, she joined me, angling across the lot. The maroon car peeled out, coming our way. The Scout was a few spaces over, in the last row of the lot. Karen and I met at the passenger door. I jerked the keys from
my pocket, sorted frantically, and fumbled the right one into the lock.

Karen climbed in. Pratt’s partner was hurrying across the last bit of pavement as fast as his stomach could shake. There was no time for me to get to the driver’s side. I pivoted and stood inside of the passenger door, pulling it most of the way closed. My posture relaxed, as if I was going to surrender to the fact the man had caught me. I gauged his approach: six feet, four, two…

I swung the door out as hard as I could. Twenty pounds of steel hit him square in the stomach and sent him sprawling to the ground. He gasped for breath. I caught the door on its way back and dove into the jeep over Karen’s lap, into the driver’s seat. She slammed the door shut and hit the lock. Again I fumbled with the keys, trying to will the tiny tip into its slot in the ignition.

By now the maroon car had arrived. It blocked my rear exit. I heard the partner gasp something to Pratt. The next moment Pratt was at my window, pounding on the glass.

“Open up!” he commanded. “Open up!”

I turned the key. The engine cranked, and cranked, and cranked. Please don’t be ornery, I pleaded.

“I’ve got mace,” Karen said.

It was the first time I’d heard her speak. Her voice was clear, pragmatic, and perfectly calm. I stared at her. She gave a little nod. Her hand was in her bag and had already closed around the canister.

“I’m going to roll down the window and duck,” I said.

She nodded again. I held my arms up in surrender to Pratt. He’d just cocked his elbow to smash in the window. “I’m opening!” I shouted.

I rolled the window down fast, inhaled, and ducked away. Karen leaned across me and gave Pratt a quick shot. He screamed and staggered against the car next to me. I rolled the window back up.

I pressed the gas pedal to the floor and cranked the ignition again. At last the engine roared to life. Over my shoulder, I saw that the partner had regained his breath and was getting into the maroon car behind us. I didn’t intend to wait to find out if he was going for a weapon.

Only one direction was open. In front of me was a high curb and a tree, about ten feet tall, newly planted on the grass embankment between the parking lot and the boulevard below. I gunned the engine and pushed the tires, in first gear, up to the curb. More gas, and they jumped it. Sad to say, the little tree wasn’t much of a match for the Scout. It cracked and went down. When my rear tires hit the curb, the jolt shot both Karen and me up out of our seats.

The Scout skidded down the grass slope. I held on to the wheel, pumped the brakes, and wrestled the jeep to the right to avoid the cars parked along the street below. Now I found myself driving down a narrow sidewalk, one wheel still angled up on the grass bank. Luckily, this was not the kind of place where people actually walked.

As soon as I found a break in the row of parked cars, I bounced down between them. When traffic was clear, I swerved onto the boulevard. I knew the maroon car would be coming out of the lot to head us off. I crossed two lanes and hit the median at an angle, jerking the left wheel up to help it over the curb. Again we were thrown into the air and pitched from side to side as the other three tires dealt with the median. Something scraped horribly on the curb as I came down into the opposite lane.

“Ouch,” I said, but still managed a smile to myself.

The Scout had come through. I accelerated and we headed away from BioVerge.

“Who are you?” Karen asked in that same steady, purposeful voice.

I looked over at her. My smile disappeared. She still had the mace in her hand, and it was pointed at me.

“Sheila tore the pages out
of her diary because she was afraid. At least, that’s my theory.”

Karen Harper paused to lift a cup of coffee to her lips. She sat across from me at a small tottery table in a cafe in downtown Santa Clara. Her blue-jeaned legs were crossed. Her finger curled around the handle. The cup was perfectly steady.

I sat facing the door of the cafe, just to be on guard. Chances were, though, that Pratt had not been able to track us through ten miles of surface streets.

“Afraid of Neil Dugan?” I asked.

“Yes. Afraid of what would happen if
anyone
found out what she was up to.”

“So, Karen, what
was
she up to?”

Karen took another sip. She had those sharp brown eyes I’d seen in the photograph at her desk. Her lips compressed in a thoughtful line. I’d told her enough about Sheila, and what had happened since her death, to convince her to keep sitting with me. I’d also hinted she might get a look at the journal.

“Sheila and I went to graduate school together. We understood each other’s style. Some of the people in mo bio are really wound up, very secretive about their work. They view every gain
you make as a loss for them. I think it’s a carryover from physics. You know, in the early part of the twentieth century, a lot of physicists got into the field. Erwin Schrödinger wrote a book called
What Is Life?
They’d gotten matter down to its basic building blocks; now they set out to do the same for life. The stakes were high. Lots of Nobel prizes. Sheila and I preferred the old, more cooperative approach. When she found some peculiar results in her program, she came to me.”

“The MC124 program. The monoclonal antibody that Frederick McKinnon designed to fight cancer.”

“Designed in a manner of speaking.” Karen’s lips curled for a moment, and then her face returned to its default expression. There was something appraising and yet plain about it, unsettling yet reassuring. Most people revealed more in their faces—softness or hardness, wariness or openness. Karen simply seemed aware.
Ready.

“McKinnon does deserve credit,” she went on. “He conceived the program, he directed the research. Sheila was loyal to him. She thought he was brilliant, and I’d guess the feeling was mutual. He was the one who’d spotted her at Stanford. But according to Sheila, it was really Doug Englehart who made the big steps in identifying the monoclonal.”

“And he’s not getting credit?”

“Not what he deserves. That’s the way it works in this business. The senior scientist takes primary authorship. Our advisor, Harry Salzmann, was different. He put us in alphabetical order. The work inspired him more than the glory. Don’t get me wrong, the work inspires the others, too. But they live for the glory.”

“And McKinnon’s got plenty of that coming. Not to mention good old cash.”

“If MC124 works. It did well in vitro and in animal tests, but you never know what will ultimately show up in the clinical trials.”

“And that’s what got Sheila worried?”

Karen nodded slowly. “I’d say so. But for the time being she was worried about a mouse. One little knockout mouse. Dead.”

“Knockout mouse?”

“A mouse with certain genes knocked out. It’s often done to determine the gene’s function. Recently it was found that a mouse lacking a gene for brain development will also keep hair longer. Whole lines of knockout mice have been created for testing purposes. RAG1 mice are immunodeficient in a way that allows tumors to grow quickly. In nude mice, the tumors can be seen growing under the skin. You can knock in genes, too. Human immune genes might be knocked into a mouse to get it to produce a more humanized antibody.”

“So a knockout mouse got knocked out in Sheila’s lab…”

“This mouse was in the trial population for MC124. Anything could have killed it. It happens all the time, you know. Organisms die. You look for the pattern. McKinnon and Englehart assumed this mouse was merely an anomaly. But Sheila thought there was something special about it. Its eyes were a little farther apart than the others. She was sure it came from a different, more humanized population than the other trial mice. If that was true, it didn’t belong in the test group. It may have been mixed in by accident. On the other hand, the humanized mice have a certain marking on their feet, which this one lacked.”

“If MC124 is fatal to human immune systems, that sounds like a problem. Did they test it on more humanized mice?”

“I assume they will. But McKinnon and Englehart are just as
sure as they can be that it’s safe. Sheila still wanted to look very closely at this particular mouse.”

“And then she got transferred out of the group.”

“Yeah. McKinnon told her she was wasting her time. Actually, it was Sheila who asked to be transferred. She never did tell me why.”

“That’s weird. Wasn’t she excited about the program?”

“Very. It was good work. I was envious.”

“What does MC124 do, exactly? What’s a monoclonal antibody?”

“MAbs, we call them. You know what an antibody is, right? It’s a type of protein that responds to an antigen—an invader—in your body by going around and tagging it for destruction. Most antibodies have a single antigen they bind to. Their molecular receptors fit each other like a lock and key. One antigen, one antibody. So you can design a MAb to hunt out and bind with certain parts of cancer cells instead of with the usual pathogens like bacteria or a virus.”

“What makes it ‘monoclonal’?”

“Mouse and rabbit populations are induced to produce the particular antibody you want. The antibody is fused with a myeloma cell. This allows you to reproduce it in what are called immortal cell lines. The antibodies are all clones. From these you derive therapeutics, such as MC124, to inject in patients. The antibody does its tagging work and recruits the immune system to attack the cancer cells. This kind of monoclonal is called a naked MAb. Others are conjugated with toxins or radioisotopes to kill the pathogens. MAbs to treat breast cancer, non-Hodgkin’s lymphoma, and transplant rejection, among other things, are already on the market.”

“It sounds like they do the same kind of thing to cancer cells that an allergic immune system does to a pollen or shellfish protein.”

“In certain ways. I always felt Sheila had her own personal reasons for getting into this field. You saw her mother at the funeral? She has lupus, which is a different kind of immune disease—autoimmune. Her system mistakes her body’s own cells for antigens. MAbs are being developed for autoimmune diseases, too.”

“I think Sheila was afraid she’d inherit it from her mother.”

“It’s certainly possible. Sheila didn’t like to talk about it, though. Maybe she opened up about it more to her diary.”

I affirmed with a nod. Karen stared into her empty coffee cup. “She had these depths of—I don’t know, pain. I tried to reach her, to be a friend. She was one of the best, the most inquiring, the most genuine people I’ve met. But she kept so much bottled inside.” Karen touched a finger to the wet corner of her eye and averted her gaze.

“I only knew her a little,” I said. “But I saw that, too.”

We sat in silence for a few moments. “Anyway,” Karen said, “monoclonals have been around for a while. They were big in the eighties: someone called them ‘magic bullets.’ Two scientists in Cambridge won a Nobel. But the drugs didn’t work the way they were supposed to in humans. Frederick McKinnon was a young dynamo at the time, poised to make a name with a small company. He had to go back to the bench before new techniques made the treatment feasible again. This is an incredible comeback for him.”

“And he wouldn’t want anyone getting in the way of it.”

“Yes, but—well, if there’s a snag, it’s going to come out sooner or later. Better sooner. The earlier problem they had with MAbs
was that they were essentially mouse antibodies. Humans in turn developed their own antibodies against the murine ones. The therapy could only be used once before the patient became ‘immune’ to it. These new monoclonals are better targeted and more highly humanized—a few of them are fully human.”

“So humanized just means the antibody is made partly of human genes.”

“Yes. You take whatever antigen you want to attack and inject it into a transgenic mouse whose immune genes are either partially or wholly human. The mouse produces the antibody, which you isolate from its spleen cells. You then fuse the antibody with human bone cancer cells, which tend to proliferate like mad. This allows the hybridoma, as it’s called, to divide and multiply. You select the most effective hybridoma culture, propagate it in the lab or in mice, and then purify your MAb from them to use as a drug.”