Knockout Mouse Read online

  “A problem with MC124 would be phenomenally inconvenient for LifeScience right now. McKinnon’s got everything riding on it. I heard him say they’re set to sign a licensing deal with Curaris on Monday. It’s already been drawing new capital to develop more programs.”

  “I hope they know what they’re doing,” Karen said. “The problem is, I’m kind of stuck. I can’t say I know for sure MC124 is dangerous until we know the origin of Smidge, the knockout mouse.”

  “That’s what I’m here for.” I drew the diary and the zip disks from a folded paper grocery bag. “The file names on these disks look promising. I also remember seeing the name Smidge in the diary. I didn’t know what it meant at the time, but I’ll go back to it.”

  Karen took the disks as if accepting a fragile specimen. “There’s a computer in the living room.”

  We moved to the next room. Karen leafed through the photocopy of Sheila’s journal while the computer booted, then put in the first of the disks. I took the diary and sat on the couch.

  “Uh huh… uh huh…” Karen repeated as she inspected the files. “Most of this data confirms what we’ve already got. It’s good, though; it gives us greater granularity on the mechanism of MC124.”

  I was working backward in the diary. “Here’s another reference to the mouse. I’ve got to make the move, or Smidge’s fate may be my own’

  Karen’s face clouded. “She was right about that one.”

  “The first time I read it, I thought Smidge might be some kind of nickname for her mother, which seemed very odd. Now I think the move she was talking about was transferring out of the MC124 group.”

  Karen nodded and punched some keys. “We’re getting warm. I’m doing a global search on Smidge’s line.” The computer hemmed and hawed. “Here we go. Yes. Databases on all the mouse lines. I wonder if Sheila had a chance to review these.”

  I kept looking through the journal. Carl Steiner’s name popped out at me. I asked Karen if she knew who he was.

  Her face was glued to the screen. “Some guy who had a crush on Sheila or something.”

  The diary entry agreed:

  Simon thinks I’m lying to him. I don’t want to stand there making excuses, like I’m guilty—yet I am guilty, he can see it. How can I possibly explain? No one wants to hear excuses, they’re boring. I’m sick of my own excuses. I should just resign myself to the nunnery of the lab. If only there was someone who understood this life, someone I could get interested in there. Aside from Carl, I mean. It’s flattering, but I have a feeling he gets a wicked crush on every new female scientist that walks in. I don’t know if I should keep accepting his little gifts. They’re almost too delicious to refuse.

  “Here we go,” Karen said. She turned in her chair. Her face had lit up in an unexpected smile. “Smidge was one of thirty-five pups in her line. The traits of the humanized population were less visible in her, but she had them: wide-set eyes, bit of white on the foot, the rest. We found it!”

  “You’re going to have to explain,” I said. “What did we just find?”

  “You need to know how Smidge was humanized,” Karen said. She stood and did a kind of two-step in front of the couch as she spoke. “Smidge was engineered to help test another antibody, one that targeted inflammation. See, there are two parts to an antibody. If you visualize an antibody as a Y-shape, one part consists of the arms. These are denoted FAb, the variable binding regions. They’re what recognize and bind to only one specific antigen. The stem of the Y is called Fc, the constant region. It calls in the body’s immune effector cells to destroy the target. It’s also the part that can be most completely humanized, as Smidge’s was. The reason you want it to be more human is so that human immune systems don’t treat the antibody itself as an invader. While the other MC124 test mice had weakened immune systems, Smidge’s was transgenically strengthened.”

  “So she should have been even better at killing tumor cells with the help of MC124.”

  Karen put her hands on her hips. “Well, her cancer wasn’t very far advanced to begin with. But this is the strange thing about MC124. Sheila confessed to me that even McKinnon wasn’t actually sure why it was so effective. Somehow the Fc region of the antibody managed to signal receptors that exist in a number of kinds of tumor cells to initiate programmed cell death, also known as apoptosis.”

  “Cell suicide.”

  “Exactly. That’s why the drug will be so huge. They weren’t sure how the apoptosis and effector cells were linked, though. They just knew the binding regions sought out the tumor receptors, and the constant region initiated apoptosis. There are ten billion cells in the immune system and complex signalling pathways we don’t begin to understand. A small inhibiting or stimulating signal can be amplified throughout the system. As long as it has no serious side effects, you’ve got a killer drug. Don’t question your good fortune, just run with it.”

  I grimaced at Karen’s double meaning. Her expression showed she was aware of it. “So MC124 is killer in more ways than one,” I said. “In most mice, it just works on tumors. But in a humanized mouse like Smidge, it makes the immune system go crazy. Which means it could do the same to human beings.”

  “Especially human beings like Sheila, whose system was already hypersensitive.”

  I shook my head. “So the cure might be worse than the disease. I can’t understand why Smidge’s death didn’t inspire LifeScience to extend the tests to humanized mice.”

  “I imagine they’re doing that next, before Phase I begins, now that they’ve established the effectiveness of MC124. I’d hope so. Even if McKinnon thinks Smidge was an anomaly, he’s got to cover himself. And if she wasn’t, I’m sure he’s counting on the dose regimen to prevent disaster. But the fact is, there’s no perfect model for treating human cancers until you get to actual clinical trials.”

  “We both suspect McKinnon is wrong,” I said. Karen nodded, and I went on, “But we need to know how and why. We need the mechanism if we’re going to take this to the authorities.”

  Karen plunked back into the computer chair. “Very good. You’re starting to think like a scientist.”

  “I’ll take that as a compliment.”

  “It is. We do need to explain how MC124 caused the reaction. Here’s what I think, based on what I’ve read in Sheila’s notebooks. The immune system has two main branches. Let’s call them Th-1 and Th-2 for short. Th-1 is involved with fighting things like viruses and cancers. Th-2 is active in allergy. Sheila speculated that something changed between mice and humans in how MC124 stimulated the immune system. Her big fear was that the Fc region changed the way signals and mediators were propagated and amplified through the network of immune cells. It turned the Th-2 branch hyper-hyperreactive.”

  “So MC124 pushed Smidge’s immune system to the edge. But what killed her?”

  “Smidge was getting a high enough dose that it could have gone off by itself. But Sheila wouldn’t have injected a proportionally heavy amount. Something still had to set it off in Sheila.”

  “Like the shellfish protein,” I said.

  Karen drummed her fingers on the table. “I’d like to know more about what the assays showed about Sheila’s blood, she said”

  “I’ve got just the woman for you. Jill Nikano, Sheila’s allergist. She’s been running more tests.”

  Karen thrust a cordless phone at me. “Call her.”

  I dug Jill’s home phone number out of my billfold. That gave me only a machine, so I tried her office number. She was there. As I began telling her what we’d discovered, Karen made grasping motions at the receiver. “Gimme.”

  “Isn’t there another phone?”

  She dashed into the kitchen. Once we got the introductions done, Karen launched into her reconstruction of Sheila’s theory. I could hear the excitement rising in Jill’s voice. “What you’re telling me makes sense with everything I’ve seen so far.”

  “She must have injected MC124,” Karen said.

  “Yes, with those
puncture marks in her arm.”

  “Any way the drug could have killed her by itself?” I asked.

  There was a silence on the other end of the line. “Noooo, I don’t think so. I’ve done immunoelectrophoresis on Sheila’s serum. I got stains for proteins whose molecular size matches shellfish allergens. There’s no doubt in my mind the anaphylactic event was induced by these proteins. MC124 may have primed her immune system, but it didn’t trigger the blow.”

  “Could it have induced a new sensitivity?” I said. “Maybe she hadn’t been allergic to salmon before, but was now?”

  “I doubt it. There’s virtually always a mild initial reaction to a new allergy before the big blow.”

  “Right,” I said. “Thanks very much, Jill. We’ll let you know as soon as we have something new.”

  “Glad to help. Say, Karen, can you email me what you’ve got?”

  Karen hesitated.

  “Not all of it is in digital form,” I said, “but we’ll send what we have.”

  As we hung up, I glanced down at my watch. It was four o’clock already, an hour past the time Wes was expecting my all-safe call. I dialed his number. Karen came in breathless from the kitchen, but when she saw I was on the phone again, she made a U-turn.

  Wes picked up. “It’s me,” I said. “Sorry I forgot to check in. I’m safe and sound.”

  I grunted apologetically as Wes listed the symptoms of anxiety he’d endured for the past hour. He’d been on the verge of phoning the police.

  “I really am sorry,” I repeated. “I meant to call you.”

  “How’s it going with Marion?” he asked out of nowhere.

  “About the same. She’s not a whole lot of help. Why?”

  “I don’t know. She called me. Got me thinking about her legs again. I guess I’m forgiven for the Brentwood stunt.”

  “It’s your love life, Wes. Just let me be the one to talk to her about what I’m up to. You know nothing.”

  “I certainly do, Damen. You’ve told me nothing except that your life is in danger. Then you forget to call. What are you chasing after, anyway?”

  “We’re getting close. I’ll let you know when we’re there.”

  “You mean Jenny’s actually following you on this goose chase?”

  “Are you kidding? No, I’ve got some expert help.”

  “I assume she’s smart, yet naive enough to join up with you.”

  “Your confidence means a lot to me, Wes. Talk to you later.”

  I joined Karen in the kitchen. She clattered the plates into the sink and angrily wrenched the tap open to rinse them. I asked what was bothering her.

  “If we don’t know how Sheila got the allergen that induced her reaction, we’re right back at the beginning!”

  “That’s not exactly true,” I said. I stacked the food cartons inside one another and tossed them into the garbage. “We know that MC124 primed Sheila’s immune system. Let’s assume for a minute that whoever gave her the antigen knew that, too. If this person was familiar with the antibody, all they had to do was give Sheila the right protein. It could have come in any form.”

  Karen put both elbows on the counter. She wedged her chin between her palms. “But what if they didn’t? What if the whole thing was just blind accident, coincidence?”

  I contemplated that void for a moment. “It was orchestrated. It had to be.”

  Karen wagged a finger at me. “Don’t make assumptions. That’s how bad science happens. Look at McKinnon. He had something to prove about MC124. It turned out he was right, but the drug might also have fatal side effects. We have to get him to open his eyes to these results. He wouldn’t before, even when Sheila pointed right at them. That’s what happens. People see what they want to see. Especially when their career is at stake.”

  “Okay, then. What I personally want to see is how Neil Dugan got that protein into Sheila’s system. It only had to be a small amount. Could there have been something in the lab—?”

  “Like a lobster tank?” Karen said sarcastically.

  “Wait a minute. They don’t have a fish farm, but LifeScience does have a farm. A big garden out back. They acquired some agri company doing transgenic plants. The corn in that garden was growing mighty high.”

  “It’s a possibility. A remote one, but still… The timing of the attack means it has to be something Sheila ate at the dinner party.”

  “What about this: What if someone at the party is working with Dugan? Fay or Marion gets the food into Sheila’s mouth that night. Dugan supplies it—the agri company was acquired under his regime, so Dugan knows its products. Fay has a motive to get back at Sheila. And Marion, I don’t know her motive, but she’s up to something.”

  Karen lifted her chin at me, a kind of challenge. “Can you get either one to talk?”

  “They’re pretty tough. I might have a spy in Marion’s house, except I’m not sure whose side he’s on.”

  Karen squinted at my remark, but let it pass. “We need people at LifeScience, people who know more.”

  “Like Carl Steiner, the gardener.”

  Karen punched my arm. “Right! Sheila’s not-so-secret admirer. She said he was a sweet guy, but—”

  I finished the sentence for her. “They’re the ones you have to watch out for.”

  27

  I had to twist Marion’s arm to get her to tell us that Carl Steiner lived in Menlo Park, which was between Redwood City and Palo Alto. She twisted back, making me promise I’d let her in on new information. I agreed to do that this evening, hoping that by then I’d be in a position to force her hand and get her to tell me what she was up to.

  Two C. Steiners were listed in the phone book. The first one, Karen and I discovered, was a young woman named Cindy who lived in an apartment complex. No relation. The other lived in a neighborhood of narrow leafy streets. The 1950s-vintage one-story house looked tired, its plaster chipping. We tried the doorbell with no result. I opened a dented aluminum screen door and pounded on the front door. Still no answer.

  We went down a walkway to the back. A tall redwood fence blocked our view of the yard. But as soon as I chinned up the fence, I knew we had the right place. “There’s a small farm back there.”

  Karen cocked her ear. “I hear digging.”

  We knocked on the fence and called Carl’s name. After about the tenth try we finally heard the click of a latch. The gate opened. Carl Steiner stood before us in a gardening cap with a giant sun bill. Fringes of brown and gray hair curled out from under the cap. He wore an ancient khaki shirt and even older pants. His shoes were covered with dirt.

  Recognition flickered in his eyes. After introducing Karen and myself, I reminded him that he and I had met at Sheila’s funeral. Steiner pulled off his gloves and put out a hesitant hand. Karen took it and turned on a charm I hadn’t seen before. Beaming at him, she said, “Sheila told me about you. She said that you were so very nice to her.”

  He turned his head and looked down at the ground. When he looked back up at Karen, he said, “She was a really special girl. It’s terrible what happened.”

  “That’s just what we wanted to ask you about,” I said. “May we come in?”

  “I suppose. Not many do. Sheila never did.” He held the gate open for us. We filed into what seemed a jungle of corn stalks, tomato plants, bean vines, and growth I didn’t recognize. It was a neat jungle, though. Narrow but well-defined paths marked the lines between each crop.

  He picked up his hoe and used it as a kind of staff as we walked. Corn stalks, now dry and stripped of their ears, rattled in the breeze. Steiner described the plants to us, their germ lines and characteristics, how they’d produced this summer, how the weather influenced the flavor. “Change coming,” he added, raising the handle of the hoe toward the cirrus clouds. “Our first rain, tomorrow maybe. Hope so. It’ll wash off the dust.”

  “I see you’ve made use of every square inch of your backyard, Mr. Steiner,” Karen remarked.

  “Just call me Car
l. You’d be amazed by my harvests. I could open a grocery store. I prefer to give it away, though.” He smiled ruefully. “Can’t eat it all myself. You like zucchini?”

  “An old favorite,” I said. “I’m surprised you grow so much here at home. Isn’t this what you do all day at work—gardening?”

  “I’ve got my degree in biology!” he objected.

  “You’re a scientist-technician,” Karen said diplomatically.

  “Exactly. I work at the bench. I work in the garden, too. Got a feel for everything we’re growing. I know more about it than any of those PhDs. You can’t replace hands-on knowledge. How a leaf smells first thing in the morning, its temper in the afternoon. These plants are my life. Why would I leave them behind when I come home?”

  “So you grow some of the company’s plants here?”

  “Just the ones we’re not actively working with.”

  We’d come to the tomatoes. I bent down to look at them. There looked to be four different varieties, each in its own plot where the south sun hit the back fence. I reached for one.

  “Don’t—don’t touch!” Carl barked.

  “Is it valuable?”

  “No, it’s just—off limits.” We looked at him, waiting for more. A ripple of anxiety slowly curdled across his face. “I didn’t develop it. The line’s from Tomagen—the company LifeScience acquired for our agri division. Best tomato you ever tasted in your life. It can grow anywhere, survive the frosts.” An unexpected bitterness came into his voice. “They call it the heart tomato.”

  He shook his hoe at the plant, as if it offended him. Some of the fruits were still mottled green and red and some were ripe enough to drop. I recognized the lovely little heart shape, about the size of a tennis ball. The film word “continuity” popped into my mind: the tomato had appeared earlier. I was trying to remember when and where. It was Jenny’s dinner party. This tomato was a perfect stand-in for the ones that Sheila had laid on the counter.

  I asked Carl delicately, “Did you know that Sheila brought some tomatoes to dinner the night she—”