by Michio Kaku
Aaby and Benn are unpopular for another reason: they have published studies suggesting that inactivated vaccines, such as DTP, have detrimental effects, particularly for girls. Even though these vaccines protect against their targeted diseases, Aaby and Benn have linked these shots to a higher risk of other infectious diseases. It is unclear why this would happen—perhaps exposure to dead pathogens makes the immune system more tolerant of other future intruders—and critics argue the associations are not just spurious but also dangerous because they could further undermine the public’s confidence in vaccines. “Some of them just think that I’m a madman making trouble,” Aaby concedes.
A Search for Clarity
His battles, however, are entering a new phase. Although Aaby notes that his own research funds are running short, the WHO says that it will soon step into the arena. Aaby first contacted the agency about his findings in 1997; in 2013 it established a working group to review the data. In 2014 the WHO noted that the issue deserved further attention, and in 2016 and 2017 it discussed plans to oversee additional trials. One trial will investigate the effects on infant mortality of giving BCG vaccination at birth versus a placebo. The other will evaluate the effects of an extra dose of measles vaccine given with DTP between twelve and sixteen months of age.
Aaby and others worry, however, that these trials will yield little clarity. The subjects will be given inactivated vaccines either at the same time as the live vaccines or after them, which, according to Aaby’s previous findings, could mute potentially beneficial effects. “We discussed this at length with many experts, and the evidence is clear that those trials will not give the answer,” Kollmann says. Shann, the Australian pediatrician, agrees. These trials will be “a scandalous waste of time and money,” he says, because “none of those involved really understands the field.” And right now it is unclear when the trials will start. WHO spokesperson Tarik Jasarevic says that as of early 2019, the agency has not found financial sponsors for the work.
Ultimately Aaby worries that the WHO is just going through the motions. He suspects the agency wants to appear that it is doing due diligence after its 2014 report on nontargeted effects but that its real goal is to make the issue go away. If nonspecific effects are real and powerful enough to save lives, then public health agencies will have to consider making changes to the vaccine schedule and perhaps even replace some inactivated vaccines with live ones, which would be extremely difficult.
Last year I asked Frank DeStefano, director of the CDC’s Immunization Safety Office, what it would take to make such changes in the U.S. “Certainly evidence would have to be stronger that this is a real effect,” he said. He noted that the agency had no plans at that time to collect more data on the issue. But even if it had additional evidence, he said, the CDC would have to consider all the possible risks and benefits before making policy changes.
The evening I left Guinea-Bissau I sat in the back garden with Benn, eating Danish cheese that she brought with her from her last trip home, and I thought about the couple’s philosophy of science. These researchers are not shy about their beliefs; they are convinced that nonspecific effects are real but so complex that many details remain a mystery, and they are not afraid to say so. To critics, this strength of conviction is a great weakness, a blazing preconception that biases their results. And it may do so. But bias is not unique to them. Scientists are people—people with ideas, and prejudices, and feelings—and every study involves interpretation. How do we know whose interpretations edge closest to the truth? Are those who admit to their beliefs more biased than those who don’t? Who should decide when enough evidence has amassed to reach a consensus, particularly when the implications are unexpected, inconvenient, and consequential? Within this small and contentious field, at least, there are no clear answers.
“You have this feeling you are pulling a thread, and you don’t know how big the ball of yarn is,” Benn said to me. She was referring to the research on vaccines, but she could have been speaking about the scientific process itself. Biology is immensely complicated because our bodies are complex. The practice of science is complicated too, because it is a product of humanity—an endeavor created and shaped by our imperfect minds. If vaccines do what Aaby and Benn think they do—and that is still an open question—it will take a lot more messy unraveling before the world sees things their way.
SIDDHARTHA MUKHERJEE
New Blood
from The New Yorker
It matters that the first patients were identical twins. Nancy and Barbara Lowry were six years old, dark-eyed and dark-haired, with eyebrow-skimming bangs. Sometime in the spring of 1960, Nancy fell ill. Her blood counts began to fall; her pediatricians noted that she was anemic. A biopsy revealed that she had a condition called aplastic anemia, a form of bone-marrow failure.
The marrow produces blood cells, which need regular replenishing, and Nancy’s was rapidly shutting down. The origins of this illness are often mysterious, but in its typical form the spaces where young blood cells are supposed to be formed gradually fill up with globules of white fat. Barbara, just as mysteriously, was completely healthy.
The Lowrys lived in Tacoma, a leafy, rain-slicked city near Seattle. At Seattle’s University of Washington hospital, where Nancy was being treated, the doctors had no clue what to do next. So they called a physician-scientist named E. Donnall Thomas, at the hospital in Cooperstown, New York, asking for help.
In the 1950s, Thomas had attempted a new kind of therapy, in which he infused a leukemia patient with marrow extracted from the patient’s healthy identical twin. There was fleeting evidence that the donated marrow cells had “engrafted” into the patient’s bones, but the patient had swiftly relapsed. Thomas had tried to refine the transplant protocol on dogs, with some marginal success. Now the Seattle doctors persuaded him to try again in humans. Nancy’s marrow was faltering, but no malignant cells were occupying it. Would the blood stem cells from one twin’s marrow “take” in the other twin?
Thomas flew to Seattle. On August 12, 1960, Barbara was sedated, and her hips and legs were punctured fifty times with a large-bore needle to extract the crimson sludge of her bone marrow. The marrow, diluted in saline, was then dripped into Nancy’s bloodstream. The doctors waited. The cells homed their way into her bones and gradually started to produce normal blood. By the time she was discharged, her marrow had been almost completely reconstituted. Nancy emerged as a living chimera: her blood, in a sense, belonged to her twin.
In 1963, Thomas moved to Seattle for good. Setting up his lab first at the Seattle Public Health Service Hospital and then, a dozen years later, at the newly established Fred Hutchinson Cancer Center—the Hutch, as doctors called it—he was determined to use marrow transplantation in the treatment of other diseases, notably leukemia. Nancy and Barbara Lowry were identical twins, and a noncancerous blood disease in one had been curable by cells from the other, a vanishingly rare occurrence. What if a disease involved malignant blood cells, as with leukemia? And what if the donor wasn’t a twin? The promise of transplantation had been hindered by the fact that our immune systems are inclined to reject matter from other bodies as foreign; only identical twins, with perfectly matched tissues, can sidestep the problem.
Thomas saw a way around this. First, he would try to eradicate the malignant blood cells with doses of chemotherapy and radiation so high that the functioning marrow would be destroyed, purged of both cancerous and normal cells. That would usually be fatal, but the donor marrow would then replace it, generating healthy new cells.
The next problems arose from trying an “allogeneic” transplant (allo, from the Greek word for “other”), using marrow from someone who wasn’t an identical twin. The resultant immune response is the consequence of an ancient system for maintaining the sovereignty of organisms. Sponges on the ocean floor use primitive versions of immune systems to reject cells from other sponges that might attempt to colonize them. Good defenses make goo
d neighbors: in nature, chimerism, the fusion of one being with another, is not a new-age fantasy but an age-old threat.
Other pioneers in organ transplantation had learned that these forces of rejection could be blunted if the donor and the host were reasonably well matched. There were now tests to help predict compatibility and to improve the chances that allogeneic marrow cells would engraft. And various immune-suppressing drugs had been developed to further dampen the host’s resistance.
Thomas, who won a Nobel Prize for these studies, later described them as “early clinical successes.” But for the nurses and the technicians in Seattle who cared for the patients—not to mention the patients themselves—the experience could be harrowing. “Of the hundred patients with leukemia who were transplanted in those early years, eighty-three died within the first several months,” Fred Appelbaum, a former student of Thomas’s, told me. Sometimes the transplanted marrow failed to take, and the patient died from anemia caused by a lack of red blood cells, or from infections caused by the paucity of white blood cells; sometimes the cancer came back. He added, “What kind of person, with that rate of failure, would perform the hundred-and-first transplant?”
The final cataclysm, in this biblical array of plagues, happened when white blood cells produced by the donor’s marrow mounted a vigorous immune response to the patient’s body. This phenomenon—called graft-versus-host disease—was sometimes a passing storm, and sometimes a chronic condition; either way, it turned the logic of immunology upside down. Typically, when foreign tissue is transplanted into a body, the fear is that the patient might reject it. But in these bone-marrow-graft cases it’s the transplant that rejects the patient. The immune cells of the bone-marrow donor—a mutinous crew forced onto an unfamiliar ship—recognize the body around them as foreign. Virtually every major organ system can fall under attack. In some cases, the disease proved fatal; in others, clinicians found ways to manage it with drugs.
In the late 1970s, Appelbaum and his colleagues analyzed the results of allogeneic transplants for leukemia, and found yet another surprise: the patients who had experienced graft-versus-host disease in its chronic form were also the ones whose cancers were least likely to relapse. The imported immune cells were effectively targeting residual cancer cells in the host. What Thomas had achieved with Lowry was akin to a regular organ transplant. (In 1954, in Boston, Joseph Murray had performed the first successful kidney transplant, also between twins.) But the phenomenon observed by doctors at the Hutch suggested that marrow grafts represented a very different kind of medical intervention.
From the start, those findings mesmerized the world of cell therapy. They showed that the human immune system—in particular, the T cell, a type of white blood cell that is central to what is known as “adaptive immunity”—could recognize and attack cancer. Which led to a question: Could T cells be trained to reject cancerous cells but not turn against the host? Could they be the basis of a new class of drug?
At this point, a larger question arises: What is a drug, anyway? A therapeutic substance, you might say. But does it have to be a molecule in its pure form, like aspirin or penicillin? Can it be a mixture of active ingredients—like cough syrup? A toxicologist might quarrel with the notion that certain substances are inherently therapeutic: water is a drug at one dose and a poison at another. Most chemotherapies are poisons even at the correct dose. Galen, the Greco-Roman physician of the second century, argued that all human pathology could be conceptualized as imbalances of humors—black bile, yellow bile, blood, and phlegm. Could a humor, drawn from a patient’s body, qualify as a drug?
For most of the twentieth century, the definition of a drug was simple, because drugs were simple: they were typically small molecules synthesized in factories or extracted from plants, purified, and packaged into pills. Later, the pharmacopoeia expanded to include large and complex proteins—from insulin to monoclonal antibodies. But could a living substance be a drug?
Thomas, who saw bone-marrow transplantation as a procedure or a protocol, akin to other organ transplants, would never have described it as a drug. And yet, in ways that Thomas couldn’t have anticipated, he had laid the foundation for a new kind of therapy—“living drugs,” a sort of chimera of the pharmaceutical and the procedural—which would confound definitions and challenge the boundaries of medicine, raising basic questions about the patenting, the manufacturing, and the pricing of medicines.
* * *
In 1971, while Don Thomas was performing his first allogeneic transplants in Seattle, an eighteen-year-old high school senior from the Bay Area named Carl June received news of his draft lottery. He had drawn the number fifty; deployment was virtually certain. So he turned down admission offers from Caltech and Stanford, and, as he likes to say, chose “the Naval Academy over the paddy fields of Vietnam.” June, who is rail-thin and lanky, with the physique of a long jumper, recalls his years at the academy with the ruefulness of an athlete forced to wait on the sidelines. After the Navy paid his way through medical school, at Baylor College, in Houston, he arrived at the Hutchinson Center, where he spent three years in the early 1980s as an oncology fellow, studying marrow transplants in Thomas’s research program. He was joining a high-powered group that included a tall, German-born rowing fanatic named Rainer Storb, who focused on tissue typing and transplant therapy; a diminutive, Siberian-born soccer enthusiast named Alex Fefer, who had shown that immune systems could turn against tumors in mice; and Thomas’s wife, Dottie, who ran the day-to-day affairs of the lab and the clinic, and whom everyone called “the mother of bone-marrow transplantation.”
June became fascinated by early experiments in transferring T cells, but then spent a decade at the Naval Medical Research Institute, in Bethesda, studying infectious diseases, such as malaria and, later, HIV. Finally, in 1999, he moved his lab to the University of Pennsylvania. His personal life, meanwhile, was crosshatched with tragedy: in 1995, his wife, Cindy, was diagnosed with ovarian cancer, and she died six years later. Throughout these years—and especially after Cindy’s diagnosis—June kept imagining a new paradigm for cancer treatment, in which living immune cells, rather than drugs, would be mobilized against the disease.
Mature T cells normally come armed with proteins on their surface—called T-cell receptors—which allow them to recognize matching bits of foreign proteins that might be present on the surface of their target cells, such as human cells infected by a virus. These receptors are notably selective: they trigger only when a cell has mounted a protein fragment on its surface and “presented” it to the T cell in the context of certain other proteins—as if they can see a picture only when the frame is right.
Unlike antibodies—Y-shaped proteins that bind like Velcro to a wide range of targets, including free-floating viruses and proteins—T-cell receptors bind to their targets somewhat loosely. The T cell can thus inspect the surface of a cell, alert others, and move on, like a drug-sniffing dog at a security checkpoint, going from one suitcase to another, summoning help where necessary.
For decades, immunologists had reasoned that the T-cell surveillance system might be able to detect and kill cancer cells. But, unlike infected cells, cancerous ones tend to be so genetically similar to normal cells, with such a similar repertoire of proteins, that they’re hard for even T cells to pick out of a crowd. A cancer-specific T-cell response could arise only if a gene were mutated or incorrectly regulated in cancer, and if the protein encoded by that gene were fragmented in the right way, and if the fragments were channeled into the cell’s system for T-cell detection, and if there were a waiting T cell equipped to sense it as foreign: a graveyard of ifs.
June knew that two researchers at the Hutch—Stanley Riddell, an animated figure with blocky glasses and a mechanical pencil habitually clipped to his shirt pocket, and Philip Greenberg, a man with a dense shag of hair that he had kept since the sixties—had begun to identify T cells that could recognize c
ytomegalovirus (a major threat to immunocompromised patients), grow those cells in flasks, and transfuse the increased population of the cells into bone-marrow recipients. In Houston, Malcolm Brenner, Cliona Rooney, and Helen Heslop had done something similar with T cells that targeted tumor cells infected by another pathogen, Epstein-Barr virus. And at the National Cancer Institute, in Bethesda, a surgical oncologist named Steven Rosenberg tried yet another strategy: he drew native T cells out of malignant tumors, such as melanomas, positing that immune cells that had infiltrated a tumor must have the capacity to recognize and attack the tumor. Rosenberg’s team grew these tumor-infiltrating lymphocytes, expanding their numbers by a few orders of magnitude, and transferred them back into patients.
There were some potent responses: 55 percent of melanoma patients treated with Rosenberg’s transferred T cells saw their tumors shrink, and 24 percent experienced a complete regression that they maintained over time. But the responses were also rather hit-and-miss. The T cells harvested from a patient’s tumor may have trained themselves to fight it, but they might also be bystanders, passive witnesses lingering at a crime scene. They might have become exhausted or inured—“tolerized” to the tumor.
