I told him. He nodded in recognition but said, “I don’t give interviews.”
“I know,” I said. “That’s okay.” Perelman and his mother stopped walking. They looked me up and down, as though what I’d said had confused them. I didn’t know how this was going to go, but at least Perelman had not run away. So I put on a big smile. “Good weather today, huh?” I said. And to my surprise, both the terrifying recluse and his nervous mother let out a laugh. They were disarmed. I was in.
“How did you know we would be here?” Lyubov Perelman asked, stepping out from behind her son. She wore thick glasses, and her cheery face puffed out beneath the beret.
“I’m embarrassed to say,” I told her.
“Well?” she said.
I nodded toward the street. “I’ve been sitting in a car out there waiting for you.”
“Really?” she said.
“It wasn’t so bad,” I said. “I had a book.”
“How did you find out the address?” Perelman asked me.
“I have a connection,” I said. “With the police.”
His eyes went wide. “The police?” he said. “Are you Russian?”
“American.”
He looked at me curiously. “Are you sure you’re not Russian?” By all signs that I could interpret, Perelman was eager to speak with me, glad for human contact.
“Do you mind if I walk with you for a little bit?” I asked. Perelman shrugged, and we kept on. He had laughed once, I thought. Maybe he would laugh again. “I was nervous,” I told him. “Everybody says you are frightening.” Perelman squinted at the sky as if contemplating something I would never understand. A man passed in front of us, walking a cat on a leash.
Lyubov Perelman said, “If you’re not getting an interview, what’s the point of this?”
Perelman put his arm around her. “It’s okay, Mother,” he reassured her. “We’re just walking.”
Considering all I had learned about Perelman, this display of considerate behavior amazed me. And it emboldened me. No one had gotten this close to him in years. “I understand you’re not practicing math anymore,” I said. “Can you tell me what you are working on?”
“I have left mathematics,” he said. “And what I’m doing now, I won’t tell you.”
I was ready with another question, but he had one of his own. “You’re really not Russian?” he asked. “You speak like someone who was born in Russia and left at eight or nine, then came back as an adult. You have this sound.”
Pressing my momentum, I asked him a few easy questions, hoping to open him up. “What are your plans for the May holidays?” “Did you enjoy your time in America?” “How often do you take these walks?” Each time, Perelman shrugged, stared into the sky, and said nothing. I wasn’t sure if he had heard me. I looked at his mother, and she raised her eyebrows as though she didn’t know what to say either. A smile crossed her face.
We made our way toward the archway that led to his entry. I tried another serious question. “Considering your abilities and how young you still are, how might you return to science?” He wheezed. After a short silence, his mother asked if I was wearing a wire.
I resolved to draw him out once more. Trying to build common ground, I touched on the similarities between writing and mathematics, emphasizing the solitude that each discipline required. I looked at him with an open, friendly face. He stared again at the sky, a blank page.
We reached the archway and stopped. Perelman and his mother stared at me, wondering how this would end. I looked at Perelman and asked, “How’s your Ping-Pong game?”
“I haven’t played in a long time,” he said. He laid an arm across his mother’s shoulders. He was becoming agitated. We had walked and talked for twenty minutes, and what had I figured out? I had gotten a feeling for the man, but I had not solved the riddle. Would he help me do it? There was time for one final question. I put it to him in English, the single philosophical question that I hoped he would consider. “Where does your life go from here?” I said.
Perelman stepped closer to me. I saw that one of his upper teeth was dark brown, decayed. “What?” he said, his English skills apparently dormant. Perelman’s face was focused in concentration as I repeated the question, and I thought that he might answer it. But when I finished speaking, his face went slack, as before. He understood what I wanted to find out, the path of this unusual life. He mumbled, “I don’t know.”
We said our good-byes.
Walking to my car, I felt as though I had failed, having gained such rare proximity to Perelman, only to have the man slip through my grasp. But then I paused, for there must have been something I had missed. Perelman was as unadorned yet just as complex as the conjecture he had proven. He had relieved the Poincaré Conjecture of its mystery, and in so doing had replaced it, becoming the puzzle himself, granting the world knowledge, yet diminishing its enchantment not at all. We don’t have to figure out everything. The unknown has its own value.
Through the windshield of the Hyundai, I watched Perelman and his mother approach their entryway, the bums and the kids and the new mothers of Kupchino going about their lives. Perelman and his mother retreated into the darkness of the vestibule. The metal door slammed closed behind them. Perelman was out, he was in. He had gotten some air.
JEROME GROOPMAN
The T-Cell Army
FROM The New Yorker
IN THE SUMMER of 1890, an adventurous seventeen-year-old from New Jersey named Elizabeth Dashiell traveled across the United States by train. During the journey, she caught her hand between the seats of a Pullman car. The hand became swollen and painful, and when it didn’t heal after she returned home, Dashiell consulted William Coley, a young surgeon in New York City. Unable to determine a diagnosis, he made a small incision below the bottom joint of her pinkie finger, where it connected to the back of her hand, to relieve the pressure, but only a few drops of pus drained out. During the following weeks, Coley saw Dashiell regularly. In the operating room, he scraped hard, gristly material off the bones of her hand. But the procedure gave only fleeting relief. Finally, Coley performed a biopsy that showed that Dashiell had sarcoma, a cancer of the connective tissue, which was unrelated to her initial injury. In a desperate attempt to stop the cancer’s spread, Coley followed the practice of the time and amputated Dashiell’s arm just below the elbow. But the sarcoma soon reappeared, as large masses in her neck and abdomen. In January 1891, she died at home, with Coley at her bedside.
After Dashiell’s death, Coley was distraught and searched through the records of New York Hospital for similar cases. He found one patient who stood out from the grim stories. Eleven years earlier, Fred Stein, a German immigrant who worked as a housepainter, had a rapidly growing sarcoma in his neck. After four operations and four recurrences of the cancer, a senior surgeon declared Stein’s case “absolutely hopeless.” Then an infection caused by streptococcal bacteria broke out in red patches across Stein’s neck and face. There were no antibiotics at the time, so his immune system was left to fight off the infection unaided. Remarkably, as his white blood cells combated the bacteria, the sarcoma shrank into a bland scar. Stein left the hospital with no infection and no discernible cancer. Coley concluded that something in Stein’s own body had shrunk the cancer.
Coley spent the next decade hoping to replicate Stein’s extraordinary recovery. In A Commotion in the Blood, published in 1997, Stephen S. Hall describes how Coley inoculated cancer patients, first with extracts of streptococcal abscesses, termed “laudable pus,” and later with purer cultures of the microbes. He claimed several successes, but the medical establishment did not embrace his approach, because his results could not be reliably reproduced. His primary critic, the pathologist James Ewing, believed that the new technique of radiation was the only scientifically sound way to treat cancer.
Coley’s work was financially supported by John D. Rockefeller Jr., a classmate of Dashiell’s brother who had considered Elizabeth his “adopted sist
er.” But Rockefeller also donated to Ewing’s research. While Coley told stories of miraculous recoveries, Ewing presented numbers that consistently demonstrated the power of radiation. Ultimately, Rockefeller chose Ewing as his scientific adviser. Rockefeller’s support led to the creation of what is now the Memorial Sloan-Kettering Cancer Center, one of the foremost institutions studying and treating malignancies. The idea that the body’s immune system could play a crucial role in eradicating cancer was largely discarded. One doctor at the time called Coley’s hypothesis “whispers of nature.”
In the last hundred years, progress in the treatment of cancer has come mostly from radiation and chemotherapy. Previously fatal blood-cell cancers, such as childhood leukemia and Hodgkin’s disease, are now curable. But solid tumors, which grow in the lungs, the colon, and the breast, have stubbornly resisted treatment once they spread beyond their initial site.
In 1971 the Nixon administration declared a “war on cancer,” promising Americans that within ten years the disease would be beaten. At the time, many researchers believed that cancer was caused by a virus that speeded up a cell’s metabolism, resulting in uncontrollable growth. After all, they had discovered some hundred viruses that caused cancer in amphibians, birds, and mammals. In the early seventies, interferon, a drug that had been developed from a protein released by white blood cells during a viral infection, was widely thought to be a possible cure for cancer; in 1980, it appeared on the cover of Time. The tumors of mice shrank dramatically when treated with the drug. But in patients interferon failed to cure solid tumors, and melanoma responded only occasionally.
Over the next decade, other proteins produced by the body as part of its immune response were made into drugs, most notably one called interleukin-2. In 1988 Armand Hammer, the ninety-year-old oil-company magnate who chaired Ronald Reagan’s cancer panel, sought to raise a billion dollars, with the aim of curing cancer by his hundredth birthday. He touted interleukin-2 as an immune booster that could achieve the goal. But most solid tumors were impervious to it, too.
In the past fifteen years, as tumors have been found to contain genetic mutations that cause them to grow unrestrained, the focus of research has shifted to cancer’s genome. Targeted therapies designed to disarm these mutations are now at the forefront of care. The first successful targeted therapy was Gleevec, which caused rapid remissions in chronic myelogenous leukemia, with few and mild side effects. Herceptin, a targeted therapy that attacks HER-2, a protein that is found in some 20 to 30 percent of breast-cancer cases, has also been effective.
Advances such as these caused Coley’s approach to fade into obscurity. Harold Varmus, a Nobel laureate and the director of the National Cancer Institute, told me that until very recently, “except for monoclonal antibodies, every therapy that exploited the immune system was pretty abysmal. There weren’t any good ideas about why immune therapy failed.” But now patients who did not respond to available therapies have shown dramatic and unexpected responses to a new series of treatments that unleash the immune system. Coley’s theories are suddenly the basis for the most promising directions in cancer research. In March 2011, the National Cancer Institute announced that it would fund a network of twenty-seven universities and cancer centers across North America to conduct trials of immune therapies. Mac Cheever, the director of the program, who is at the Fred Hutchinson Cancer Research Center in Seattle, described it as a way to speed the practical work of developing treatments. “All of the components needed for effective immunotherapy have been invented,” he said.
Jim Allison, the director of the tumor-immunology program at Memorial Sloan-Kettering, began his career as a researcher at the University of Texas Cancer Center in 1978. At the time, he was taken with the idea that the T cell could be directed against cancers. T cells, a potent type of white blood cell, destroy cells infected with microbes that they recognize as foreign. The immune system uses a variety of white blood cells to fight disease. Some, like neutrophils and macrophages, engulf and chew up microbes. In contrast, T cells attack the microbe from the outside, with a fusillade of enzymes. Cancers disarm the immune system, producing proteins that cause T cells to either quickly become exhausted and die or blithely overlook the tumor. Allison’s research focused on why T cells failed either to recognize cancer as being aberrant or to attack it, as they do with microbes.
Allison’s mentors discouraged him from pursuing research on T cells. “Tumor immunology had such a bad reputation,” he told me when we met in December at his laboratory at Sloan-Kettering, which overlooks the East River. Allison, who is sixty-three years old, is a thickset man with a stubbly beard and a gravel voice. “Many people thought that the immune system didn’t play any role in cancer.” Treatments like interferon and interleukin-2 had led scientists on a roller coaster of hype followed by disappointment. Immune therapy was also tainted by popular claims that following a certain diet or reordering your mind could be natural immune-boosting ways to cause tumors to disappear, with none of the miserable side effects of chemotherapy and radiation.
But Allison started looking at how the immune system fights disease, using mice as study models, and capitalized on a critical discovery: T cells require two signals to attack a target effectively. The first signal, he said, was “like the ignition switch,” and the second “like the gas pedal.” When working against a microbe, both signals were operative. But in the presence of cancer, “T cells don’t get those signals to attack,” he explained. Allison started to wonder what it would take to reliably activate the immune system against cancer.
In 1987 researchers in France discovered a protein called cytotoxic T-lymphocyte antigen-4, or CTLA-4, which protruded from the T cell’s surface. “There was a real race among a number of labs to figure out its function,” Allison recalled. A scientist at Bristol-Myers Squibb, using results from his lab, contended that CTLA-4 increased the activity of T cells and the immune system. But Allison and Jeffrey Bluestone, an immunologist, obtained results from independent experiments that contradicted that conclusion. Allison and Bluestone believed that CTLA-4 actually acted as a brake on the T cells, and Allison thought that it might be keeping the immune system from attacking tumors. “Jeff and I were kind of in the wilderness for a while,” Allison said. “Before this, people just thought that T cells died on their own.” He speculated that treatments designed to activate the immune system might have failed because the treatments were actually stimulating CTLA-4. As Allison put it, “We ought to free the immune system, so it can attack tumor cells.”
Allison’s postdoctoral researchers implanted cancer cells under the skin of mice, some of which were then treated with an antibody that blocked CTLA-4. After several weeks, the cancers disappeared. One of the researchers showed Allison the data in early December 1995. Allison was astounded. The lab was about to go on Christmas break, but he wanted to repeat the experiment immediately. “I told the researcher that he should inject the tumors into a new group of mice, and have a control group that didn’t get the antibody. And I’d measure the tumors myself,” Allison recalled. “So it was really a blinded experiment, because I didn’t know what was what.” A week later, Allison measured the cancers. “The tumors were still growing, and I’m starting to despair. And then, in half of the mice, the tumors just seemed to stop, but in the other half of the group they kept going. And then in the ones in which it stopped, the cancer started disappearing and just went away.” Allison added, “It immediately confirmed our original assumption that this could be good for any kind of cancer.”
For two years, as Allison continued his experiments on mice, he approached pharmaceutical and biotech companies for help in developing the treatment for patients, but he was repeatedly turned away: “People were skeptical of immunology and immune therapy. They would say, ‘Oh, anybody can treat cancer in mice.’ Sometimes they’d say, ‘You think you can treat cancer by just removing this negative signal on a T cell?’”
Allison also learned that Bristol-Myers Squibb
had filed for a patent asserting that CTLA-4 stimulated T-cell growth. “If that was the case, you would never, ever think about injecting an antibody that blocked CTLA-4 into a cancer patient, because it would make things worse,” he said. “People were scared of putting that into a patient.” But Allison persisted, telling industry executives that Bristol-Myers Squibb was wrong. Finally, he persuaded a small company called Medarex to invest in the approach.
Among its first trials on humans, in 2001, Medarex included patients with malignant melanoma, because it was one of the few cancers that had occasionally responded to immune-based treatments like interferon or interleukin-2. In pilot studies, patients were treated with the antibody to CTLA-4, and, as in mice, the cancers continued to grow for some weeks before a few of the tumors shrank. In 2004 Bristol-Myers Squibb formed a partnership with Medarex to collaborate on the drug. A subsequent trial showed scant impact after twelve weeks. Many of the tumors got bigger, and in some patients new lesions appeared. Pfizer was also testing an antibody to CTLA-4 and concluded that it was a failure; the trial was stopped early.
Months after the end of the Bristol-Myers Squibb study, however, several of the clinicians involved, including Jedd Wolchok, of Memorial Sloan-Kettering, and Stephen Hodi, of the Dana-Farber Cancer Institute in Boston, realized that the tumors had either stopped growing or begun to shrink. Wolchok and his colleagues prevailed upon Bristol-Myers Squibb to include overall survival rates of patients after several years. (Because the established criteria for judging the effectiveness of chemotherapy drugs are based on the first months of treatment, the trial had been considered a failure.) “It was pretty courageous,” Allison said, “because it would take a long time to finish the study.” In June 2010, the results were presented at the annual meeting of the American Society of Clinical Oncology. Although the drug had extended the patients’ lives a median of only four months, nearly a quarter of the patients were alive two years into the trial. Their predicted survival had been seven months. “This is a drug unlike any other drug you know,” Allison said. “You are not treating the cancer—you are treating the immune system. And it was the first drug of any type to show a survival benefit in advanced-melanoma patients in a randomized trial.”
The Best American Science and Nature Writing 2013 Page 15