Authors: James Calder
“I’m
on
it, Frederick.” Doug’s voice was curt. “Please, just leave me to do my work.”
Even from my position on the couch, I could feel the tension. All conversation had ceased. I pictured the two men glaring at each other, McKinnon towering erect and imperious, Doug bristling below.
Doug came into the office a moment later. He closed the door, then paced the small area in front of his desk.
“You need a bigger office,” I said.
He froze and stared me. “I’m getting one.”
“Once MC124 is a success?”
“Very soon.”
“I imagine that will put you on more equal footing with Dr. McKinnon. You two have been very close, haven’t you?”
He turned away and began to straighten papers. “I was his grad student. It’s long past time for me to have a program of my own.”
“Will you still be working with monoclonal antibodies?”
He spun on me. “What do you care? Just tell me what Frederick said to you!”
“He said he’s tested MC124 on himself to prove its safety. I thought that was noble of him.”
Doug stretched his neck and scratched. He had some kind of rash under his jowl. “I’ve tested it, too, but I don’t go around bragging about it.”
“Did Sheila?”
“Maybe Frederick tricked her into it,” he said after a pause. “Did Neil Dugan know about this?”
Doug shook his head slowly. “No one did. You shouldn’t either. What do you want, anyway?”
“I just want to know what killed Sheila.”
His forehead bunched again. “All right. I’ll see what I can find out. I’ll check up on Dugan. But not until after Monday.”
“Anything helps. I have some notes from Sheila—”
His eyes widened and the phone buzzed at the same instant. Doug picked it up. “Yeah, I talked to him. No, he’s not here. Yeah, I know what he looks like.”
He put down the phone. “Dugan. He’s looking for you.”
I stood up. Doug appraised me for a minute, then said, “Go back down the corridor to the center of the building. Past the elevators, into the wing opposite this one. Turn right. Look for a stairway. It’ll take you down to the atrium. Turn left and go out the door in the back. A guard will be watching for you at the front.”
“Thanks. Do you have a cell phone?”
He scribbled the number on the back of his card. I took it and took off. The stairway was where he said it would be. I went down the stairs and opened the door into the atrium very slowly. The guard, near the reception desk, was looking the other way. I slid out and walked quickly toward the back exit. The guard called to me as I got to the door. I picked up my pace.
The door led onto a patio bordered by a line of raised flower beds. I stepped around them and broke into a run. I had to turn right to get around the annex, the agri division, which stood between me and my car. As I came around the blind corner, I nearly ran straight into a high wire fence around a garden tall with corn. I cut left into the parking lot and got in the Scout. As I was backing up, I saw the guard huffing his way around the building. By the time he yelled at me to stop, I was already pulling away.
Karen answered the door
in shorts and a red T-shirt. She was hiding out at her friend’s condo in Redwood City, about five miles north of Palo Alto. Yesterday, she and a posse of friends had managed to rescue her car from Gregory’s lot and to retrieve Sheila’s leather bag from Karen’s apartment. I thought it was a good idea for her to stay put for a while. I was more concerned than ever that Dugan and Pratt were hunting for her, and I’d watched to make sure no one was following me as I drove over. Scrutinizing my rearview mirror had become second nature lately.
The condo’s owner had gone out for the day. On a table in a nook of the kitchen, Karen had spread what Sheila had given her: notebooks, disks, and printouts. I’d brought the diary and the zip disks from their hiding place in the Scout. We sat next to the humming refrigerator. Karen plunked some leftover Chinese food and a Coke in front of me and said, “So what did you get?”
I told her about my visit to LifeScience. “McKinnon had a strong case for MC124 being safe. Both he and Doug Englehart tested it on themselves. The autopsy said Sheila had needle puncture marks in her arm. Doug as much as admitted she’d been dosed too.”
Karen shook her head in disapproval. “She should’ve told me about it. Then again, she knew what I’d say. I would have chewed her out. She might have felt like she had no choice but to test it.”
“To keep her job?”
“To keep McKinnon’s respect. To show her loyalty to the team. There’s an intense togetherness on a project like that. Sheila cared so much about being part of it. She cared what McKinnon thought of her.”
“Well, her injecting it cuts both ways,” I said. “On the one hand, I want to look even harder at MC124. On the other, the fact that her two superiors have tried it and are fine so far means it’s a less likely cause of her death.”
Karen stopped with a string of noodles in front of her mouth. “Wait a minute. What does this remind you of?”
“Someone about to make a big slurping sound?”
Karen went ahead and slurped. “It reminds you of the knockout mouse. One died. The others that we know of are fine.”
“Right. The question is, what is it that got that one?”
We sat for a minute, pondering the mouse. The only insight that came to me was that it was time for lunch. I shoveled some food onto a plate, then managed to spray soy from a little packet onto a printout.
“Try to control yourself,” Karen said in a dry voice.
“It’s a boy thing,” I said. Then a small pang hit me as I recalled my dinner conversation with Sheila.
“Are you all right?”
I shook it off. “Tell me what you’ve learned about this mouse.”
“I’ve combed through Sheila’s research. MC124 was being tested on three populations. One was mice with tumors. Another was mice without tumors, a control group. A third was a population with and without tumors that was receiving high doses
of MC124. The focus in that group was toxicity. Our knockout mouse was in the third group. Sheila named her Smidge because she had just a smidgen of white on her back foot. The necropsy showed the mouse was strangled by her own immune system. Doug declared that she’d simply been overdosed or had a reaction to some other antigen. It didn’t matter which, because it was an anomaly: no other mice died. Sheila wondered if the problem had more to do with the bit of white on the foot.”
“What does the foot have to do with it?”
“Very little, of course, except that the white was a marker. It designated a mouse population that was humanized. Smidge had a number of mouse immune genes knocked out and human ones knocked in. Sheila conjectured that a technician put Smidge in the wrong cage because the white mark on her foot was so small. You could easily miss it.”
“How sure are you that Smidge didn’t belong in the test population? If the marking was so clear on the others but not on her, maybe she was in the right place after all.”
“You’re right. That’s the biggest flaw in Sheila’s hypothesis, and the biggest question we have to answer. Anyway, McKinnon backed Doug’s interpretation. He said fine, at worst it means we need to be careful about the dose regimen. The lower dose seemed to do the job on tumors, so there was nothing to worry about. Sheila thought that conclusion was a little too convenient.”
“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?”