“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?”