The Best American Science and Nature Writing 2020

by Michio Kaku

  “Some of these responses don’t last—​there’s resistance—​and it’s a big goal in the field to find the cause of resistance,” June said. “We still have to run rigorous randomized studies to determine if the therapies are effective, and whether they are cost-effective, and whether they can be delivered at scale. But would you rather push the boundaries of a partially effective cellular therapy, acknowledging all its problems, yet also recognizing its clear responses? Or would you rather pay a million dollars for ineffective chemotherapies, only to pay again for cellular therapy?”

  Yet June saw a downside to the fact that cellular therapies were classified as drugs: it could hinder their incremental improvement. “In the current regulatory environment, the FDA approves drugs on a one-by-one basis,” he observed. Procedures represent a history of small, iterative improvements. But, if you tweak the substance of a cellular therapy, it’s officially a different drug, which has to undergo another gauntlet of trials and agency reviews, a costly and time-consuming process.

  I asked June if he foresaw the price of the drugs coming down. “It’s all going to be about automation and manufacture,” he told me. “If a drug remains out of the reach of the patients who really need it, why even call it a drug?”

  * * *

  It isn’t until you witness the production of an individualized cell therapy that you grasp the scale of the challenge. At about eight o’clock on a Tuesday morning last fall, I visited the Hutch and accompanied Bruce Thompson, the scientific manager, and James Adams, the operations head, as they descended two floors, into the cell-processing facility in the E sub-basement. Behind wire-mesh glass, the facility’s rooms were painted a fluorescent green. “We all agreed on the color, but now we all agree that we dislike it,” Adams told me, ruefully.

  I asked Thompson if I could go inside, explaining that I’d been growing human cells in sterile media for more than a decade. Thompson looked at me, unmoved. He is about forty-five, broad-shouldered and soft-spoken, with the gentle but unbending manner of a vault manager at Cartier. “We have very strict anticontamination rules,” he said. “And doctors who treat the patients here are especially discouraged from walking in and out of the facility.”

  Instead, I watched through the windows as a technician named Houman Bashiri—​in dark-blue scrubs, elastic booties, and a mask—​reached into an incubator, took out a flask, and held it to the light. The fluid inside was orange and turbid, with hundreds of thousands of engineered T cells. The cells had been doubling every day, Thompson said. In about a week’s time, they would be infused into the patient, where, if all went well, they would multiply even more, kill malignant cells, and then remain in the body, on guard, to survey the tissues and fight any recurrence of cancer.

  The facility had thirty-five incubators, eight centrifuges, and six sterile hoods, where the cells are inspected and manipulated. Every time Bashiri added a drop of a chemical—​a growth factor, say—​he announced the action out loud. A second technician checked the chemical against the protocol and marked it off in a binder, in a maddeningly methodical process meant to guarantee that each action performed on the cells was documented and cross-checked.

  I spoke later with Thompson and Adams. “If living cells are to become drugs, they have to be manufactured under standard protocols, like drugs,” Thompson said. “This caused tensions between the facility technicians and the doctors—​and the tensions still continue.” Most of the doctors who ran the studies, or treated patients with the approved cell therapies, had been trained as bone-marrow transplanters. They’d spent much of their careers steeped in the experimental and artisanal nature of the craft. “They were used to looking at their cells every day, and then deciding when to infuse them,” Thompson went on. “One of them might come down one afternoon and say, ‘Oh, the cells don’t look quite ready yet. Why don’t we give them another two days and a little squeeze of a growth factor?’”

  But each departure from the standard operating practice had the potential of violating a clinical protocol. There has to be a rule, as it were, against exceptions. What’s more, untidiness, in this endeavor, can have grave consequences. “Each patient gets his or her own private incubator,” Adams said. “That way, we can never contaminate one patient’s cells with another’s”—​a mix-up that could be fatal—​“or mistake one for another.” When one patient is done, the incubator is sterilized. “The suite is cleaned weekly by a specialized crew,” he said. “And once a year we close down the whole facility for a top-to-bottom inspection.”

  The protocols were rigorous, and yet they could not have been further from the efficiencies of mass manufacture. In this sense, CAR-T still resembles a procedure, like a mastectomy or a liver transplant; it’s a matter of painstaking craft. A few months ago, at the Cleveland Clinic, in Ohio, I watched a cardiothoracic surgeon perform a four-hour operation to replace a patient’s leaky heart valve. It was a breathtakingly elegant procedure. Each move was meticulously orchestrated and controlled. The surgeon opened a fish-mouth-shaped hole in the aorta and began to stitch in the new valve. Members of the operating team assisted one another in a precise choreography. Whenever someone new entered the room, he or she checked a list to make sure that no protocol had been violated.

  For all this precision, however, other aspects of the operation—​call them the factory-floor aspects—​went undiscussed. I heard no one speak about whether the plastic in the tubing equipment could have been optimized to cut costs. Or whether the team could have worked more efficiently by altering the distance between the hooks where the sterile equipment hung. Or whether the eight-odd minutes it took to put on a gown and scrub hands could have been reduced. Would some intervention in a small, repetitive action have saved a few minutes of operating time so that, added up, the surgeon might be able to operate on one more patient a week?

  In medical school in the 1990s, I took classes on the economics of health. I learned about the overuse of medical services, the skyrocketing prices of prescription medicines, and the disparities in access to medical care that such pricing worsened. Distinctions were made between the price of a drug (how much a payer is charged for medicine), its cost (how much it takes to develop and manufacture that medicine), and its value (the actual benefit that a patient receives from a drug or procedure).

  But nowhere in these lessons did I encounter the Japanese term kaizen—​the continuous improvement of a manufacturing process to its leanest, most efficient form. It would have been a worthwhile lesson. Engineers in the world of industrial manufacturing obsess about this. But as doctors, as medical scientists and inventors, we are taught to think about curing deadly diseases or about creating new systems of care. We want to battle the mortal coil, not the plastic coil. We want to close the gaps in access to medical care, not the gaps between hooks in the operating room. We give priority to proofs of principle, not to the particularities of production. Yet, if the newest generations of therapies are to succeed at scale, it may be the small skirmishes that determine the outcome of the larger war. For cellular therapy to reach the masses, its innovators cannot ignore the most trivial-seeming details of the human and material factors of the manufacturing process. Perhaps we need a change in our culture, or even in our vocabulary. In Cleveland, as in operating theaters around the world, the clinicians were in yarak. The new generation of medical care will be enabled by the ceaseless demands of kaizen.

  * * *

  A few days after my visit to Cleveland, I flew back to New York. At my laboratory at Columbia, Florence Borot, a postdoctoral scientist originally from Paris, is exploring another way to scale up cellular therapy. A major challenge in the manufacture of CAR-Ts is the exquisitely bespoke nature of their production: right now, every “living drug” has to be made out of a patient’s own cells. Borot is trying to engineer T cells so that they might be transferred from a donor to a patient who isn’t an immunological match. Borot has a knack for immunological sleight of hand: she hunts through the genome to
find factors that enable immune recognition and then, using new genetic technologies, makes them disappear without compromising the functions of the T cells. Variations of this strategy are being attempted by dozens of other scientists, in universities and at biotech companies. The ultimate aim is to create the so-called universal T cell—​a cell that has the capacity to engraft in any person’s body. These cells could be grown en masse, frozen, and shipped from a central facility to a patient’s hospital room.

  A second approach creates a drug from a patient’s own circulating T cells, but without needing to manipulate and multiply them. An engineered molecule, called a bi-specific T-cell engager (BiTE is the trade name of Amgen’s candidate), is designed to tether a T cell to a cancer cell (hence “bi-specific”), and trigger an immune response to the cancer. These molecules would be infused into a patient and engage circulating T cells already present in the patient’s blood and lymph nodes. Such T-cell engagers are currently being tested against various cancers in human trials. And there are other strategies for reducing the costly complications of “living drugs.” An effort I’m involved in would genetically modify a leukemia patient’s noncancerous B cells, or other white blood cells, to shelter them from the effects of CAR-T. If only the cancerous cells were eradicated, the treatment would not damage the immune system, currently its most long-lasting side effect.

  The number of cell-therapy researchers, meanwhile, seems to double and redouble week by week. We present our data at conferences dedicated solely to cell engineering. We discuss methods to equip T cells or natural-killer cells with permanent immunological memory, so that they remain on constant guard against relapses of the cancer. We study ways of amplifying the effect of CAR-T therapy by combining it with checkpoint inhibitors, drugs that first became available less than a decade ago and prevent tumor cells from impeding T-cell activity. We analyze mechanisms of resistance—​like the occasional appearance of leukemic B cells that don’t display CD19—​and try to engineer CAR-T cells that will not release the cytokine storms that nearly killed Bill Ludwig and Emily Whitehead.

  Through all these exuberant discussions, however, the questions of manufacture and scale linger. Even the most radically innovative methods will need continuous, iterative improvements to make them affordable. We like to imagine medical revolutions as, well, revolutionary—​propelled forward through leaps of genius and technological innovation. But they are also evolutionary, nudged forward through the optimization of design and manufacture. There is a fair degree of humility in this knowledge, which a new generation of cell therapists is slowly absorbing.

  * * *

  On a blustery afternoon in May, I attended a conference on cellular therapy, titled “CAR-T and the Rise of Cellicon Valley,” at the University of Pennsylvania, which it had co-organized with CHOP. Nearly 1,000 scientists, doctors, and biotech executives converged on a soaring auditorium on Spruce Street, lugging posters in plastic tubes and discussing the next waves of treatment.

  Among those in attendance was Emily Whitehead, now fourteen, a year older than my daughter. She has tousled brown hair, and is in her eighth year of remission. “She was happy to miss a day of school,” her father told me. She sat in the front row, in a yellow-and-black shirt and dark pants. Emily was eager to take in the latest medical breakthroughs in cellular therapies; she was also looking forward to a celebratory lunch at Pod, a pan-Asian restaurant where the dumplings, apparently, are also a breakthrough.

  During a pause in the sessions, Emily and I joined a tour of the medical campus led by Bruce Levine, one of June’s colleagues. He is the founding director of the facility at Penn where T cells are modified, quality-controlled, and manufactured, and was among the first people to handle Emily’s cells. As in Seattle, the Philadelphia technicians worked singly or in pairs, checking boxes, taking cells out of incubators for observation, sterilizing hands.

  The facility may as well have been a small monument to Emily. Photographs of her plastered the walls: Emily at eight, in pigtails; Emily at nine, with a missing front tooth, smiling next to President Obama; Emily at ten, holding a plaque. At a certain point during the tour, I watched Emily look out the window to the hospital across the street. She could almost see into the corner PICU room, where she had been confined for nearly a month. The rain came down in sheets.

  I wondered how she felt, knowing that there were three versions of her in the hospital: the one here today, on a break from school; the one in the pictures, who had lived and almost died in the PICU; and the one frozen in the Krusty the Clown freezer next door. A chimeric existence of sorts.

  “Do you remember coming into the hospital?” I asked.

  “No,” she said, looking out into the rain. “I only remember leaving.”

  DOUGLAS PRESTON

  The Day the Dinosaurs Died

  from The New Yorker

  If, on a certain evening about 66 million years ago, you had stood somewhere in North America and looked up at the sky, you would have soon made out what appeared to be a star. If you watched for an hour or two, the star would have seemed to grow in brightness, although it barely moved. That’s because it was not a star but an asteroid, and it was headed directly for Earth at about 45,000 miles an hour. Sixty hours later, the asteroid hit. The air in front was compressed and violently heated, and it blasted a hole through the atmosphere, generating a supersonic shock wave. The asteroid struck a shallow sea where the Yucatán peninsula is today. In that moment, the Cretaceous period ended and the Paleogene period began.

  A few years ago, scientists at Los Alamos National Laboratory used what was then one of the world’s most powerful computers, the so-called Q Machine, to model the effects of the impact. The result was a slow-motion, second-by-second false-color video of the event. Within two minutes of slamming into Earth, the asteroid, which was at least 6 miles wide, had gouged a crater about 18 miles deep and lofted 25 trillion metric tons of debris into the atmosphere. Picture the splash of a pebble falling into pond water, but on a planetary scale. When Earth’s crust rebounded, a peak higher than Mount Everest briefly rose up. The energy released was more than that of a billion Hiroshima bombs, but the blast looked nothing like a nuclear explosion, with its signature mushroom cloud. Instead, the initial blowout formed a “rooster tail,” a gigantic jet of molten material, which exited the atmosphere, some of it fanning out over North America. Much of the material was several times hotter than the surface of the sun, and it set fire to everything within 1,000 miles. In addition, an inverted cone of liquefied, superheated rock rose, spread outward as countless red-hot blobs of glass, called tektites, and blanketed the Western Hemisphere.

  Some of the ejecta escaped Earth’s gravitational pull and went into irregular orbits around the sun. Over millions of years, bits of it found their way to other planets and moons in the solar system. Mars was eventually strewn with the debris—​just as pieces of Mars, knocked aloft by ancient asteroid impacts, have been found on Earth. A 2013 study in the journal Astrobiology estimated that tens of thousands of pounds of impact rubble may have landed on Titan, a moon of Saturn, and on Europa and Callisto, which orbit Jupiter—​three satellites that scientists believe may have promising habitats for life. Mathematical models indicate that at least some of this vagabond debris still harbored living microbes. The asteroid may have sown life throughout the solar system, even as it ravaged life on Earth.

  The asteroid was vaporized on impact. Its substance, mingling with vaporized Earth rock, formed a fiery plume, which reached halfway to the moon before collapsing in a pillar of incandescent dust. Computer models suggest that the atmosphere within 1,500 miles of ground zero became red hot from the debris storm, triggering gigantic forest fires. As the Earth rotated, the airborne material converged at the opposite side of the planet, where it fell and set fire to the entire Indian subcontinent. Measurements of the layer of ash and soot that eventually coated the Earth indicate that fires consumed about 70 percent of the world’s forests. Meanwhil
e, giant tsunamis resulting from the impact churned across the Gulf of Mexico, tearing up coastlines, sometimes peeling up hundreds of feet of rock, pushing debris inland, and then sucking it back out into deep water, leaving jumbled deposits that oilmen sometimes encounter in the course of deep-sea drilling.

  The damage had only begun. Scientists still debate many of the details, which are derived from the computer models, and from field studies of the debris layer, knowledge of extinction rates, fossils and microfossils, and many other clues. But the overall view is consistently grim. The dust and soot from the impact and the conflagrations prevented all sunlight from reaching the planet’s surface for months. Photosynthesis all but stopped, killing most of the plant life, extinguishing the phytoplankton in the oceans, and causing the amount of oxygen in the atmosphere to plummet. After the fires died down, Earth plunged into a period of cold, perhaps even a deep freeze. Earth’s two essential food chains, in the sea and on land, collapsed. About 75 percent of all species went extinct. More than 99.9999 percent of all living organisms on Earth died, and the carbon cycle came to a halt.

  Earth itself became toxic. When the asteroid struck, it vaporized layers of limestone, releasing into the atmosphere a trillion tons of carbon dioxide, 10 billion tons of methane, and a billion tons of carbon monoxide; all three are powerful greenhouse gases. The impact also vaporized anhydrite rock, which blasted 10 trillion tons of sulfur compounds aloft. The sulfur combined with water to form sulfuric acid, which then fell as an acid rain that may have been potent enough to strip the leaves from any surviving plants and to leach the nutrients from the soil.