Forty Signs of Rain

  Frank scrolled down the pages of the application with practiced speed. Yann Pierzinski, Ph.D. in biomath, Caltech. Still doing postdoc work with his thesis advisor there, a man Frank had come to consider a bit of a credit hog, if not worse. It was interesting, then, that Pierzinski had gone down to Torrey Pines to work on a temporary contract, for a bioinformatics researcher whom Frank didn’t know. Perhaps that had been a bid to escape the advisor. But now he was back.

  Frank dug into the substantive part of the proposal. The algorithm set was one Pierzinski had been working on even back in his dissertation. Chemical mechanics of protein creation as a sort of natural algorithm, in effect. Frank considered the idea, operation by operation. This was his real expertise; this was what had interested him from childhood, when the puzzles solved had been simple ciphers. He had always loved this work, and now perhaps more than ever, offering as it did a complete escape from consciousness of himself. Why he might want to make that escape remained moot; howsoever it might be, when he came back he felt refreshed, as if finally he had been in a good place.

  He also liked to see patterns emerge from the apparent randomness of the world. This was why he had recently taken such an interest in sociobiology; he had hoped there might be algorithms to be found there which would crack the code of human behavior. So far that quest had not been very satisfactory, mostly because so little in human behavior was susceptible to a controlled experiment, so no theory could even be tested. That was a shame. He badly wanted some clarification in that realm.

  At the level of the four chemicals of the genome, however—in the long dance of cytosine, adenine, guanine, and thymine—much more seemed to be amenable to mathematical explanation and experiment, with results that could be conveyed to other scientists, and put to use. One could test Pierzinski’s ideas, in other words, and find out if they worked.

  He came out of this trance of thought hungry, and with a full bladder. He felt quite sure there was some real potential in the work. And that was giving him some ideas.

  He got up stiffly, went to the bathroom, came back. It was midafternoon already. If he left soon he would be able to hack through the traffic to his apartment, eat quickly, then go out to Great Falls. By then the day’s blanching heat would have started to subside, and the river’s gorge walls would be nearly empty of climbers. He could climb until well past sunset, and do some more thinking about this algorithm, out where he thought best these days, on the hard old schist walls of the only place in the Washington D.C. area where a scrap of nature had survived.

  Mathematics sometimes seems like a universe of its own. But it comes to us as part of the brain’s engagement with the world, and appears to be part of the world, its structure or recipe.

  Over historical time humanity has explored farther and farther into the various realms of mathematics, in a cumulative and collective process, an ongoing conversation between the species and reality. The discovery of the calculus. The invention of formal arithmetic and symbolic logic, both mathematicizing the instinctive strategies of human reason, making them as distinct and solid as geometric proofs. The attempt to make the entire system contained and self-consistent. The invention of set theory, and the finessing of the various paradoxes engendered by considering sets as members of themselves. The discovery of the incompletability of all systems. The step-by-step mechanics of programming new calculating machines. All this resulted in an amalgam of math and logic, the symbols and methods drawn from both realms, combining in the often long and complicated operations that we call algorithms.

  In the time of the development of the algorithm, we also made discoveries in the real world: the double helix within our cells. DNA. Within half a century the whole genome was read, base pair by base pair. Three billion base pairs, parts of which are called genes, and serve as instruction packets for protein creation.

  But despite the fully explicated genome, the details of its expression and growth are still very mysterious. Spiraling pairs of cytosine, guanine, adenine, and thymine: we know these are instructions for growth, for the development of life, all coded in sequences of paired elements. We know the elements; we see the organisms. The code between them remains to be learned.

  Mathematics continues to develop under the momentum of its own internal logic, seemingly independent of everything else. But several times in the past, purely mathematical developments have later proved to be powerfully descriptive of operations in nature that were either unknown or unexplainable at the time the math was being developed. This is a strange fact, calling into question all that we think we know about the relationship between math and reality, the mind and the cosmos.

  Perhaps no explanation of this mysterious adherence of nature to mathematics of great subtlety will ever be forthcoming. Meanwhile, the operations called algorithms become ever more convoluted and interesting to those devising them. Are they making portraits, recipes, magic spells? Does reality use algorithms, do genes use algorithms? The mathematicians can’t say, and many of them don’t seem to care. They like the work, whatever it is.

  LEO MULHOUSE kissed his wife Roxanne and left their bedroom. In the living room the light was halfway between night and dawn. He went out onto their balcony: screeching gulls, the rumble of the surf against the cliff below. The vast gray plate of the Pacific Ocean.

  Leo had married into this spectacular house, so to speak; Roxanne had inherited it from her mother. Its view from the edge of the sea cliff in Leucadia, California, was something Leo loved, but the little grass yard below the second-story porch was only about fifteen feet wide, and beyond it was an open gulf of air and the gray foaming ocean, eighty feet below. And not that stable a cliff. He wished that the house had been placed a little farther back on its lot.

  Back inside, fill his travel coffee cup, down to the car. Down Europa, past the Pannikin, hang a right and head to work.

  The Pacific Coast Highway in San Diego County was a beautiful drive at dawn. In any kind of weather it was handsome: in new sun with all the pale blues lifting out of the sea, in scattered cloud when shards and rays of horizontal sunlight broke through, or on rainy or foggy mornings when the narrow but rich palette of grays filled the eye with the subtlest of gradations. The gray dawns were by far the most frequent, as the region’s climate settled into what appeared to be a permanent El Niño—the Hyperniño, as people called it. The whole idea of a Mediterranean climate leaving the world, even in the Mediterranean, people said. Here coastal residents were getting sunlight deficiency disorders, and taking vitamin D and antidepressants to counteract the effects, even though ten miles inland it was a cloudless baking desert all the year round. The June Gloom had come home to roost.

  Leo Mulhouse took the coast highway to work every morning. He liked seeing the ocean, and feeling the slight roller-coaster effect of dropping down to cross the lagoons, then motoring back up little rises to Cardiff, Solano Beach, and Del Mar. These towns looked best at this hour, deserted and as if washed for the new day. Hiss of tires on wet road, wet squeak of windshield wipers, distant boom of the waves breaking—it all combined to make a kind of aquatic experience, the drive like surfing, up and down the same bowls every time, riding the perpetual wave of land about to break into the sea.

  Up the big hill onto Torrey Pines, past the golf course, quick right into Torrey Pines Generique. Down into its parking garage, descending into the belly of work. Into the biotech beast.

  Meaning a complete security exam, just to get in. If they didn’t know what you came in with, they wouldn’t be able to judge what you went out with. So, metal detector, inspection by the bored security team with their huge coffee cups, computer turned on, hardware and software check by experts, sniff-over by Clyde the morning dog, trained to detect signature molecules: all standard in biotech now, after some famous incidents of industrial espionage. The stakes were too high to trust anybody.

  Then Leo was inside the compound, walking down long white hallways. He put his coffee on his desk, turned on his
desktop computer, went out to check the experiments in progress. The most important current one was reaching an endpoint, and Leo was particularly interested in the results. They had been using high-throughput screening of some of the many thousands of proteins listed in the Protein Data Bank at UCSD, trying to identify some that would activate certain cells in a way that would make these cells express more high-density lipoprotein than they would normally—perhaps ten times as much. Ten times as much HDL, the “good cholesterol,” would be a lifesaver for people suffering from any number of ailments—atherosclerosis, obesity, diabetes, even Alzheimer’s. Any one of these ailments mitigated (or cured!) would be worth billions; a therapy that helped all of them would be—well. It explained the high-alert security enclosing the compound, that was for sure.

  The experiment was proceeding but not yet done, so Leo went back to his office and drank his coffee and read Bioworld Today on-screen. Higher throughput screening robotics, analysis protocols for artificial hormones, proteomic analyses—every article could have described something that was going on at Torrey Pines Generique. The whole industry was looking for ways to improve the hunt for therapeutic proteins, and for ways to get those proteins into living people. Half the day’s articles were devoted to one of these problems or the other, as in any other issue of the newszine. They were the recalcitrant outstanding problems, standing between “biotechnology” as an idea and medicine as it actually existed. If they didn’t solve these problems, the idea and the industry based on it could go the way of nuclear power, and turn into something that somehow did not work out. If they did solve them, then it would turn into something more like the computer industry in terms of financial returns—not to mention the impacts on health of course!

  When Leo next checked the lab, two of his assistants, Marta and Brian, were standing at the bench, both wearing lab coats and rubber gloves, working the pipettes on a bank of flasks filling a countertop.

  “Good morning guys.”

  “Hey Leo.” Marta aimed her pipette like a Power-Point cursor at the small window on a long low refrigerator. “Ready to check it out?”

  “Sure am. Can you help?”

  “In just a sec.” She moved down the bench.

  Brian said, “This better work, because Derek just told the press that it was the most promising self-healing therapy of the decade.”

  Leo was startled to hear this. “No. You’re kidding.”

  “I’m not kidding.”

  “Oh not really. Not really.”

  “Really.”

  “How could he?”

  “Press release. Also calls to his favorite reporters, and on his webpage. The chat room is already talking about the ramifications. They’re betting one of the big pharms will buy us within the month.”

  “Please Bri, don’t be saying these things.”

  “Sorry, but you know Derek.” Brian gestured at one of the computer screens glowing on the bench across the way. “It’s all over.”

  Leo squinted at a screen. “It wasn’t on Bioworld Today.”

  “It will be tomorrow.”

  The company website’s BREAKING NEWS box was blinking. Leo leaned over and jabbed it. Yep—lead story. HDL factory, potential for obesity, diabetes, Alzheimer’s, heart disease …

  “Oh my God,” Leo muttered as he read. “Oh my God.” His face was flushed. “Why does he do this?”

  “He wants it to be true.”

  “So what? We don’t know yet.”

  With her sly grin Marta said, “He wants you to make it happen, Leo. He’s like the Road Runner and you’re Wile E. Coyote. He gets you to run off the edge of a cliff, and then you have to build the bridge back to the cliff before you fall.”

  “But it never works! He always falls!”

  Marta laughed at him. She liked him, but she was tough. “Come on,” she said. “This time we’ll do it.”

  Leo nodded, tried to calm down. He appreciated Marta’s spirit, and liked to be at least as positive as the most positive person in any given situation. That was getting tough these days, but he smiled the best he could and said, “Yeah, right, you’re good,” and started to put on rubber gloves.

  “Remember the time he announced that we had hemophilia A whipped?” Brian said.

  “Please.”

  “Remember the time he put out a press release saying he had decapitated mice at a thousand rpm to show how well our therapy worked?”

  “The guillotine turntable experiment?”

  “Please,” Leo begged. “No more.”

  He picked up a pipette and tried to focus on the work. Withdraw, inject, withdraw, inject—alas, most of the work in this stage was automated, leaving people free to think, whether they wanted to or not. After a while Leo left them to it and went back to his office to check his e-mail, then helplessly to read what portion of Derek’s press release he could stomach. “Why does he do this, why why why?”

  It was a rhetorical question, but Marta and Brian were now standing in the doorway, and Marta was implacable: “I tell you—he thinks he can make us do it.”

  “It’s not us doing it,” Leo protested, “it’s the gene. We can’t do a thing if the altered gene doesn’t get into the cell we’re trying to target.”

  “You’ll just have to think of something that will work.”

  “You mean like, build it and they will come?”

  “Yeah. Say it and they will make it.”

  Out in the lab a timer beeped, sounding uncannily like the Road Runner. Meep-meep! Meep-meep! They went to the incubator and read the graph paper as it rolled out of the machine, like a receipt out of an automated teller—like money out of an automated teller, in fact, if the results were good. One very big wad of twenties rolling out into the world from nowhere, if the numbers were good.

  And they were. They were very good. They would have to plot it to be sure, but they had been doing this series of experiments for so long that they knew what the raw data would look like. The data were good. So now they were like Wile E. Coyote, standing in midair staring amazed at the viewers, because a bridge from the cliff had magically extended out and saved them. Saved them from the long plunge of a retraction in the press and subsequent NASDAQ free fall.

  Except that Wile E. Coyote was invariably premature in his sense of relief. The Road Runner always had another devastating move to make. Leo’s hand was shaking.

  “Shit,” he said. “I would be totally celebrating right now if it weren’t for Derek. Look at this”—pointing—“it’s even better than before.”

  “See, Derek knew it would turn out like this.”

  “The fuck he did.”

  “Pretty good numbers,” Brian said with a grin. “Paper’s almost written too. It’s just plug these in and do a conclusion.”

  Marta said, “Conclusions will be simple, if we tell the truth.”

  Leo nodded. “Only problem is, the truth would have to admit that even though this part works, we still don’t have a therapy, because we haven’t got targeted delivery. We can make it but we can’t get it into living bodies where it needs to be.”

  “You didn’t read the whole website,” Marta told him, smiling angrily again.

  “What do you mean?” Leo was in no mood for teasing. His stomach had already shrunk to the size of a walnut.

  Marta laughed, which was her way of showing sympathy without admitting to any. “He’s going to buy Urtech.”

  “What’s Urtech?”

  “They have a targeted delivery method that works.”

  “What do you mean, what would that be?”

  “It’s new. They just got awarded the patent on it.”

  “Oh no.”

  “Oh yes.”

  “Oh my God. It hasn’t been validated?”

  “Except by the patent, and Derek’s offer to buy it, no.”

  “Oh my God. Why does he do this kind of stuff?”

  “Because he intends to be the CEO of the biggest pharmaceutical of all time. Like he told P
eople magazine.”

  “Yeah right.”

  Torrey Pines Generique, like most biotech start-ups, was undercapitalized, and could only afford a few rolls of the dice. One of them had to look promising enough to attract the capital that would allow it to grow further. That was what they had been trying to accomplish for the five years of the company’s existence, and the effort was just beginning to show results with these experiments. What they needed now was to be able to insert their successfully tailored gene into the patient’s own cells, so that afterward it would be the patient’s own body producing increased amounts of the needed proteins. If that worked, there would be no immune response from the body’s immune system, and with the protein being produced in therapeutic amounts, the patient would be not just helped, but cured.

  Amazing.

  But (and it was getting to be a big but) the problem of getting the altered DNA into living patients’ cells hadn’t been solved. Leo and his people were not physiologists, and they hadn’t been able to do it. No one had. Immune systems existed precisely to keep these sorts of intrusions from happening. Indeed, one method of inserting the altered DNA into the body was to put it into a virus and give the patient a viral infection, benign in its ultimate effects because the altered DNA reached its target. But since the body fought viral infections, it was not a good solution. You didn’t want to compromise further the immune systems of people who were already sick.

  So, for a long time now they had been in the same boat as everyone else, chasing the Holy Grail of gene therapy, a “targeted nonviral delivery system.” Any company that came up with such a system, and patented it, would immediately have the method licensed for scores of procedures, and very likely one of the big pharmaceuticals would buy the company, making everyone in it rich, and often still employed. Over time the pharmaceutical might dismantle the acquisition, keeping only the method, but at that point the start-up’s employees would be wealthy enough to laugh that off—retire and go surfing, or start up another startup and try to hit the jackpot again. At that point it would be more of a philanthropic hobby than the cutthroat struggle to make a living that it often seemed before the big success arrived.