Eternal Sonata

by Jamie Metzl

  Still no action from the warehouse.

  I connect with Joseph, who shows me what more he’s learned about the impressive careers of Professor Hart, Dr. Wolfson, and Dr. Heller.

  Still nothing from the warehouse.

  It’s getting dark, and I’m starting to wonder if I’m really achieving anything by lurking around. But I’ve already sunk five hours into this stakeout and I still have ninety minutes before I need to be at Toni’s. If I leave now, I’ll have to start over from scratch. I eat a SaladBar from my glove compartment and wait.

  Nothing.

  I’m trapezing between consciousness and a daydream inexplicably involving Martina, Sierra, and my mother at the Santa Monica pier when my partly opened eyes send an urgent alert to my brain. My head jerks forward.

  The light is not perfect, but even in the hazy sunset the outline of the tall, older man is clear. As he strides toward the river, I see the silhouette of an excited puppy leaping around him.

  I open my car door as quietly as possible and step out, then walk briskly over and approach him from behind.

  Dr. Livingstone, I presume? I reject the impulse. “Excuse me. I’m sorry to bother you.”

  The man turns abruptly. He is lanky and thin with a wisp of gray hair resting over his forehead. His large eyes alight his creased face over ruddy cheeks. An unmistakable vibrancy counteracts his advanced age. “Who the hell are you?” he says in a staccato that sounds British but I know to be South African.

  “Dr. Heller?”

  A worried, almost panicked, look crosses the man’s face. “So this is it?” he asks gravely.

  “I’m sorry?” I say, confused.

  He stares at me sharply for a few moments before seeming to process my obliviousness. Then he takes a step backwards, turns, and begins marching briskly toward the warehouse. “Sebastian, come,” he orders over his shoulder to the small brown Labrador.

  “I’m very sorry to bother you, Dr. Heller,” I say, rushing behind him. “I need to ask you some questions.”

  “Please leave me alone,” he says nervously, picking up his pace.

  “But …”

  The imposing back door to the warehouse opens. The puppy is at first uncooperative, twisting its head toward me and bouncing back and forth between the sources of duty and excitement. Heller turns, perturbed, and ushers the exuberant puppy in the door.

  “Dr. Heller, I need to talk with you,” I say into the swiftly closing door. I hear the lock turn. “Dr. Heller.”

  14

  Toni disliked the idea from the moment I raised it.

  I’d rushed in her door at 8:20 with grilled chicken and a carton of steamed vegetables so I was already halfway in the doghouse.

  But for Toni there are worse places than the doghouse. “It’s dishonest and deceptive,” she’d said, “and I doubt it will work. From everything you’ve told me about him, Dr. Heller will see right through it.”

  She may have been right, but I can be a dogged pain in the rear sometimes and here I am at 6 a.m. back in my same West Bottoms hiding place with a still somewhat hormonal low-boil Toni in the passenger seat of my car, two large travel mugs of espresso, and Toni’s mother’s biscuit-tan cocker spaniel, Dreyfus, slobbering up the bio-sympathetic hatch of my Tesla.

  The car is one of my few indulgences with the nearly $200,000 I earned from Genesis Code. I remind myself daily that the sleek, rocket-like sports car is just a frivolous object, but I’m honest enough to recognize I’ve developed almost romantic feelings for it. The temperature-controlled, body-forming seats ensure perfect comfort in my little ecosystem. The full-screen dashboard fully integrates with my u.D. The constant stream of augmented reality updates describing conditions ahead and potential dangers flashes across my windshield. The internal lighting system and selections from my music playlist correspond with biometric data constantly monitored from my wrist. When I sit back and give over control to the Autonomous Driving System, I feel cared for, safe.

  But after paying all of Maya’s baby costs, helping Joseph build a small school in his home village in Kerala, buying a gold and sapphire necklace for Toni, and putting some money away for our long-planned but—thanks to me—not-yet-realized big trip to “someplace hot,” and throwing down more than I probably should have for this irresistibly indulgent sports car, I now find myself with $46,000 in the bank and not much more long-term security than I had two years ago.

  On another day it could almost be romantic, sitting in the car watching the blending orange and purple hues of the sun rising over the Missouri, reflecting on the fall leaves dangling from the few trees lining the banks of the mighty river. But today we wait quietly, and Toni stews.

  I’ve learned the hard way over the years that there are some things I do well and some things not so well. I can dazzle people with intellect or, as is painfully obvious right now, overcome their resistance with a mix of idealism and pugnacity, but I don’t have the simple ability to make people I’ve just met trust or sometimes even like me.

  Toni, on the other hand, is a natural genius at this. Her calm manner and deep Midwestern graciousness almost magically put people at ease. She connects. It’s not only what makes her so good at her job, it’s also why the world, which sometimes feels charged and tense around me, seems more at ease around her. She, of course, knows all of this. It’s just that she doesn’t like her best qualities being used as a prop, or her love and knowledge of dogs being woven into another of my schemes.

  The plan, I think as I look at jovial Dreyfus in the rearview mirror, isn’t entirely contemptible. And Dreyfus, my unwitting agent, is quite simply the most likable dog I’ve ever met. Even I, who somehow lack the pet-obsessed gene most everyone else in America seems to possess, have a soft spot in my heart for Dreyfus. Floppy-eared, with a constant look of excited expectation on his face, his expression and demeanor, if verbalized, would probably translate into something like “oh boy, really, can I, can I?” It’s hard to imagine any man or beast not taking pity on poor, needy Dreyfus, who seems to want only to be loved, and granting him at least a few moments of sympathetic attention.

  After forty or so minutes of waiting, we see the two figures emerging from the back door of the warehouse. Heller is walking, erect and brisk, with Sebastian darting peripatetically around him.

  “Told you,” Toni says proudly. “Puppies have to make kaka and run around in the morning.”

  “You were right and you are on,” I say.

  She eyes me with a mix of annoyance and appreciation.

  “And thank you,” I add.

  She shakes her head. “Come on, Dreyfus. Let’s do this.”

  Dreyfus has less appreciation that he’s being exploited. He lifts his head excitedly at the sound of his name. Dreyfus? Hey. That’s me. Oh boy, really, can I, can I?

  I watch them walk around the building to approach Heller from the other side. I see Dreyfus sprinting over to Sebastian and the two dogs first sniffing each other and then leaping and yelping together, their tails wagging excitedly. Then Heller moves briskly toward the dogs and Toni follows suit. I see them start talking.

  At first Heller’s body stands stiff and erect, but as the minutes pass his stiffness seems to melt. After about fifteen minutes, I see him nod slightly. Toni bows her head as if to say thank you before Toni and Heller begin walking toward me. I get out of the car as they approach.

  “Rich, this is Dr. Noam Heller. Dr. Heller, this is Rich Azadian.”

  “I’m sorry about yesterday,” I fumble.

  Dr. Heller looks at me as if sizing me up, then scans the horizon in both directions with an expression that seems, for a moment at least, somehow nervous. “Why don’t the two of you come in.”

  15

  Stepping through the substantial door of the decaying warehouse, I am overwhelmed.

  From the look of the building’s exterior I would have expected some dusty boxes and a few battered remnants of better days. Instead, the glistening, fully automated, sta
te-of-the-art laboratory blows me away.

  The immaculate white walls gleam under incandescent light. Immense cabinets, looking like glass refrigerators filled with test tubes and agar plates, line the wall to my left. Near them, a massive cart is stacked with hundreds of small plastic cubbies, a white mouse twitching in each. A series of conveyor belts, reminding me of one of those endless sushi bars, runs from each of these areas toward the middle of the room, where an outsized scope rests under a translucent plastic dome.

  To my right, clear plastic sheeting walls off fifteen or so compact machines arrayed in a rectangle. Inside the rectangle, quietly whirring yellow robotic arms pull plastic plates in and out of each machine in a symphony of coordinated movement. Each time an arm reaches over, a small window opens on each machine, allowing the plates to be transferred from one to the other.

  At the far end of the lab, a massive silver door makes the smaller white door next to it look downright Lilliputian. The violin sonata playing in the background only heightens my sense of bizarre juxtaposition. It’s hard to grasp so much happening in so concentrated a space.

  “Incredible.” The quiet word leaks from my mouth. I hardly notice Dreyfus and Sebastian nipping each other happily as they race toward the far corner of the lab.

  “Welcome to Heller Labs,” Heller says, the wrinkles around his eyes contracting warmly. He is not at all young but there is definitely a certain youthfulness about him.

  “I don’t know where to begin,” I say awkwardly, still trying to get a handle on what I’m seeing and wondering why he has let us enter in the first place.

  Toni steps in. “Thank you again for inviting us in.”

  “You didn’t give me much a choice,” Heller says with a hint of irony.

  “I mentioned to you outside that I’m a nurse, but I’ve never seen a lab quite like this.”

  “Why, thank you. I don’t get many visitors. It’s nice to show off a bit.”

  “Would you mind showing off a little more?” she asks.

  Heller’s slight blush is momentarily overcome by what seems almost like a flash of worry. “I normally would not be so forthcoming,” he says, composing himself, “but you’ve come at what we might call a serendipitous moment.” He looks down for a few seconds as if figuring something out, then stares at each of us in turn before taking a few steps toward the glass cabinets. “It all starts over here.”

  Toni glances at me and raises her eyebrows as we follow Heller. Not bad for a walking hormone machine.

  I smile back with my eyes. Thank you.

  Heller opens one of the cabinet doors, picks up an agar plate, and holds it out to us. We train our eyes on the layer of murky white gel.

  “Look closely,” he says, moving it under a light.

  “Everything is moving,” Toni says.

  “Exactly. Caenorhabditis elegans, but most people call these amazing creatures roundworms.” He pauses theatrically. “I began studying them many years ago with the great Sydney Brenner. They are the little workhorses of biomedical research—the size of a standard comma, the simplest little creatures with a nervous system. They’re hermaphroditic, cheap, freezable, and most importantly, short-lived.”

  “Sucks for them,” I say.

  Heller looks at me and smiles thoughtfully. “We all live on borrowed time, Mr. Azadian, but our lives exist on a relative scale. The C. elegans normally live about two weeks, but I’m quite confident their experience feels as long to them as ours does to us.”

  “Or as short,” I add, my perennial fear of mortality triggered.

  My words seem to catch Heller’s attention. He pauses, as if processing a thought. “We all live on sliding scales.”

  Toni and I look at him expectantly.

  Heller hesitates, as if unsure he should continue.

  “How do you mean?” Toni coaxes.

  An avuncular half smile builds slowly on his face. “The mice over here generally live an average of 2.3 years. The bats that swarm over the river at night can live up to fifty years. Why?”

  We don’t have an answer.

  “It’s not an easy question,” Heller continues, “but essentially regulatory proteins tell hormones to instruct cells what to do. For the past decade, I’ve been studying how roundworms with specific genetic mutations and extra doses of certain molecules regulating their cells can live longer than normal. I’m trying to gain insights into how we might reprogram cancer cells to their younger, healthier state. Roundworms are simple creatures, far simpler than humans, but we have many of the same genes and can learn a lot about ourselves by studying them. Like all organisms, their cells are constantly balancing how much energy to allocate to growing versus to repairing themselves. That’s the balance of nature. If they put more resources into growing, they put less into repair and live shorter lives. The inverse is also true. It’s all regulated by insulin signaling between the cells. That’s the great insight of the C. elegans research.”

  “So if all you eat is sugar, you live hard and die young,” I say, my eyes glancing over and briefly catching Toni’s.

  “Something like that. If we suppress the insulin receptor, the daf-2 gene, they get less of that sugar high and live longer. The same effect happens if we boost the daf-16 gene and make them emphasize cellular repair. But worms don’t have stem cells like higher-level organisms, so there’s only so much they can tell us about cancer cells.”

  Toni and I nod slightly, encouraging Heller to continue.

  Heller leads us toward the mouse cart. “So the next logical question I asked was whether the same mutation process would work on a far more sophisticated mammal, our little furry friends over here. In addition to boosting and suppressing the daf genes, I experimented with a number of approaches. I’m not sure if these words mean anything to you, but I explored rapamycin and everolimus kinase inhibition, sirtuins, telomerase therapy. Each is a different way of sending signals to the cell that emphasize repair. Everything worked a little. Nothing worked well. I tried delivering a chemical into the cells called nicotinamide adenine dinucleotide, NAD, to reverse the decay of their mitochondria, the little power packs of the cell. The process worked a bit better but with a twist. The mice with the mutated genes and NAD injections lived slightly longer, but they became far more susceptible to other diseases like diabetes. A number of them grew uncontrollable tumors. My fight to stop cancer was instead enabling it. Something was missing.”

  My mind wanders back to the bleak images of human wreckage from the Kansas City and St. Louis hospices. “I’m sure I didn’t understand all of it,” I interject, “but I read your article from six years ago in the Journal of Regenerative Medicine.”

  “That article was mostly theoretical when I wrote it. I hadn’t actually proven anything. I just outlined the idea of using a combination of genetic manipulations and other approaches to reverse-age specific cancer cells. I needed to see if the mutations and other inputs that slowed the deterioration of the roundworm and mouse cells could be used to target cancer cells in higher-level mammals.”

  “And that’s what you’ve been working on here?” Toni asks.

  “Let me show you something else,” Heller says, leading us toward the rectangle of machines inside the plastic sheeting. “This process is called quantitative high throughput screening. The different machines wash, incubate, sort, spin, and sequence the cells. We can sequence the DNA of the roundworms or the mice or anything else. We can reprogram blood cells into stem cells and then differentiate them into other types of cells. In a day, we can do what it would have taken a lab worker fifteen years a couple of decades ago.”

  “And with that you can cure cancer?” Toni asks.

  “That has always been the goal, but it’s an extremely difficult one.” Heller looks solemnly at Toni, then slowly shifts his gaze to me, as if again weighing whether he should continue. He takes a deep, slow breath. “There are many types of cancer cells, but the ones we worry about all have one very basic hallmark. They’ve esse
ntially forgotten how to die and are multiplying out of control, overcoming the body’s natural immunological ability to fight back. We’ve gotten pretty good at identifying cancers these past years through liquid biopsies pinpointing the nucleic acids circulating in the bloodstream. For years we’ve also been making progress in fighting cancers through precision molecular medicine, checkpoint inhibitors, immunotherapy, antibody-drug conjugate therapies and the like, but we’re always a day late and a dollar short because the cancers keep evolving and mutating. But cancer is ultimately a disease of cellular aging, so I wanted to stop trying to figure out how to fight each different cancer and instead focus on reverting the biological age of the cells to a point in time before they became cancerous.”

  “To slow their aging process like you did with the roundworms?” Toni asks.

  “Even more,” Heller says. “Slowing the cell’s aging process wasn’t enough. Once they were cancerous, the cells had their own internal accelerators.” Heller pauses again before continuing. “My idea, my big idea, was to not just try to revert specific cells to a previous state but to also amplify the naturally occurring genes known to suppress the growth of the cancer, to send the cells back in time and give them a better chance of defending themselves going forward.”

  “Can cells really go back in time?” I ask.

  “People didn’t used to think so before Yamanaka cracked the code for inducing stem cells, but humans are far more plastic than we once thought.”

  My mind jumps back from the fascinating science lecture to the urgency of this moment. “So when did Santique find you?” I ask.

  Heller’s face tightens. “They didn’t exactly find me. I’d known them for a while and our interests were dovetailing. They offered me a great deal of money and to build me this facility if I would join them.”