The Final Experiment
In early 2007 Steinman was away in Colorado at a scientific meeting, a trip that he had turned into a family ski vacation, when he and his twin daughters all had what seemed like a stomach bug. His daughters recovered quickly, but his illness lingered. Soon after he returned home, he developed jaundice. In the third week of March he went in for a CT scan, and radiologists found a tumor in his pancreas. By then, it had already spread to his lymph nodes. He knew his odds of survival were slim: about 80 percent of pancreatic cancer patients die within a year.
“When he first told us, he said, ‘Do not Google this—just listen to me,’” his daughter Alexis recalls. She felt like someone had punched her. “He really expressed to the family that while it was a very drastic disease, he was in a very good position,” she says. Unlike the average cancer patient, Steinman had access to many of the top immunologists and oncologists on the planet—and, perhaps even more important, to their most promising therapies.
When Schlesinger heard the news, she was devastated. And she quickly rallied to her mentor’s side. She, Steinman, and their close Rockefeller colleague Michel Nussenzweig began making phone calls, sharing the news with colleagues across the globe. Steinman was convinced that the surest way to be cured of any tumor was to develop immunity against it through his own dendritic cells. They had a limited amount of time to prove him right.
One of the early calls Steinman made after his diagnosis was to his longtime collaborator Jacques Banchereau, who now directs the Baylor Institute for Immunology Research in Dallas. Banchereau then picked up the phone to call Baylor researcher Anna Karolina Palucka, who had known Steinman since the 1990s. Although she had an experimental vaccine in the works that she thought could help Steinman, she struggled with the personal challenge of trying “to compartmentalize the friend, the patient, and the scientist.”
For her part, Schlesinger called Charles Nicolette, a friend and collaborator of many years and the chief scientific officer of Argos Therapeutics, an RNA-based drug company in Durham, North Carolina, that Steinman had cofounded. Nicolette, reeling from the news, mobilized his own colleagues within minutes of hanging up the phone.
Nicolette’s group had developed a dendritic cell vaccine that was in a phase II (intermediate-stage) clinical trial to treat advanced kidney cancer. Argos’s therapy endeavors to enlist a patient’s own dendritic cells against a cancer by exposing them to genetic material from the tumor, which induces them to rally T cells to mount a proper attack.
Steinman was scheduled to have part of his pancreas removed during the first week of April 2007—a surgery known as a Whipple procedure, which is part of a more traditional treatment for his prognosis. Nicolette would need part of that tumor to draw up his vaccine, which left him just days to get the U.S. Food and Drug Administration to approve Steinman’s entry into his trial, permission the team was able to secure just in time.
With the tumor cells secured and while the Argos treatment was brewing, a process that would take months, Steinman started in on other therapies. Soon after his surgery, he went on standard Gemcitibine-based chemotherapy, and then, in the late summer, he enrolled in a trial of GVAX, a dendritic cell–based vaccine that was being tested to treat pancreatic cancer. Codeveloped by Elizabeth Jaffee of Johns Hopkins University and administered at the Dana-Farber/Harvard Cancer Center, the vaccine uses a generic tumor antigen, as the Provenge prostate cancer vaccine does. In an earlier phase II trial, pancreatic cancer patients who had received the vaccine lived an average of four months longer than those who had not, and some ended up living for years. So for two months, starting in the late summer, Schlesinger traveled with Steinman to Boston almost every week. “I remember walking in Boston on a day like this,” she says, looking out of her corner office window into the clear, paling blue October afternoon sky, “thinking, He’s not going to see another fall, and I was so sad.”
But fall came and went, and Steinman remained in relatively good health. In September 2007 he received the Albert Lasker Award for Basic Medical Research, considered by many to be a precursor to the Nobel, and he sat for a series of video interviews. In them he elaborated on the promise of dendritic cells to fight cancer, noting that an immune attack is highly directed, highly specific, and, unlike chemotherapy, nontoxic. “I think this provides the potential for a whole new type of therapy in cancer,” he said. “But we need research and patience to discover the rules, to discover the principles.”
At times Steinman showed more patience than his colleagues would have liked. He had initially argued for a very slow course of treatment for himself so that his team could monitor his immune response after each therapy before beginning the next. But Schlesinger and Nussenzweig eventually convinced him that they simply did not have the time. If he died, the experiment and data collection were over.
By November 2007 the Argos vaccine, made by infusing cells taken from Steinman’s blood with genetic material extracted from his tumor, was ready and waiting. Steinman had just finished with a chemo treatment, and he enrolled in Argos’s renal-cell carcinoma trial under a single-patient study protocol.
In early 2008 Steinman followed up with Palucka’s vaccine, which was being developed for melanoma. It incorporated a selection of tumor-specific peptides (protein fragments), so she suspected it could be repurposed to target Steinman’s cancer by using peptides from his tumor in place of antigens from melanoma.
Other offers for experimental treatments poured in from all over the world. “Everybody who could brought the best they could,” Palucka says. Steinman’s decades of collegial work had united the field, and now that network of scientists turned to help one of their own. “People think of science as a solitary process. In fact, it’s an extremely social process,” Schlesinger says. The “social nature of our work facilitated the forthcoming of these tremendous intellectual resources.”
In addition to standard treatment, Steinman ended up enrolled—under a special patient provision—in four ongoing clinical trials of various dendritic cell–based cancer treatments, most of which were not even being tested for pancreatic cancer, along with several other experimental immunotherapy and chemo treatments. Schlesinger, a member of the Rockefeller Institutional Review Board (IRB), steered his treatment through all the necessary IRB and FDA channels, making sure the standard protocols were followed. She also personally gave Steinman his vaccines whenever they could be administered at Rockefeller.
Steinman ran his own grand experiment the way he ran others in the lab—always carefully collecting data, evaluating the evidence, and doling out instructions. Schlesinger still has e-mail chains from the period, Steinman’s messages coming back in all capital letters per his style. He kept particularly close tabs on how his own body was responding to treatment. In 2008, during his time on Palucka’s therapy, she came for a visit to New York City. After Schlesinger had given Steinman his dose of the vaccine, the three of them went out to dinner. On finishing their meal, Steinman insisted they stop by Palucka’s hotel so that he could show them the welt developing on his leg around the injection site. “He was so enthused about it,” Schlesinger says. “He said, ‘Those are T cells’”—indicating that his body was having an immune response to the vaccine—“‘that’s great!’”
The local swelling showed that Steinman’s body was reacting to the vaccine, although, Palucka says, she cannot be certain it was tumor-specific T cells that had been mobilized. As she points out, all vaccines work through dendritic cells, but the difference with her therapy and the others that Steinman tried was that rather than leaving exposure up to chance, researchers manipulated the dendritic cells outside of the body to improve the odds that they would train T cells to attack the tumor. When Schlesinger was not on hand to see the evidence for herself, she says, “he would send me these descriptions of the vaccination sites with great enthusiasm,” including information about the appearance and size of the sites—and even how each one felt.
His tum
or marker, the level of a protein that indicates the progress of a cancer (which fluctuated throughout the course of his treatment), became a barometer for his attitude. The second time the marker went down, he sent an e-mail out with the subject line “We’ve repeated the experiment,” the glee of which was apparent to those who knew his joy in a scientific triumph.
But the good news that satisfied Steinman the patient was never good enough to satisfy Steinman the scientist. The knowledge that his one-person experiment was hardly a scientific one frustrated him no end. With the experimental treatments administered so close to one another—and interspersed with traditional chemotherapy—it was impossible to know what sent his tumor biomarker downward.
Nevertheless, Steinman generated some interesting data points along the way. During one of Palucka’s immune-monitoring tests during his treatment, she found that some 8 percent of cells known as CD8 T cells (also called killer T cells) were specifically targeted to his tumor. That might not sound like a lot, but given all the potential pathogens that the body can encounter and mount an attack against, 8 percent “is a huge number,” Schlesinger says. “So something immunized him—or some combination of things immunized him.”
A Death, Days Too Soon
Steinman and his wife, Claudia, traveled to Italy to celebrate their fortieth wedding anniversary in June 2011—just two months after what he referred to as his fourth “Whipple-versary,” in honor of his April 2007 surgery. Already he had far surpassed the average survival of a person with his type of cancer.
In mid-September 2011, Steinman was still working at the lab, and arrangements had been made for him to restart the Argos treatment. Then Steinman fell ill with pneumonia. “When he was admitted to the hospital, he said, ‘I might not make it out of here,’” Alexis recalls. But after her father’s four and a half years of good health, she found it hard to believe she would have only days left with him. He was still reviewing data from Rockefeller as late as September 24. On Friday, September 30, he died at the age of sixty-eight from respiratory failure caused by pneumonia, which his cancer-weakened body could no longer fend off.
His family struggled with how to even begin to tell his vast network of friends and colleagues around the globe. They planned to visit his old lab—where he had been working until so recently—to tell those there on Monday, October 3. But early that morning, before any of them were awake, Stockholm called. Steinman’s BlackBerry, on silent, was with his wife. In a fitful early-morning sleep, she glanced over to see a new-message light blinking. Just then an e-mail popped up, politely informing Steinman that he had won the 2011 Nobel Prize in Physiology or Medicine.
The first response was that “we all collectively screamed the ‘f’ word,” Alexis says. Her next thought was “Let’s go wake up Dad.”
But for the rest of the world, nothing about the Nobel committee’s announcement seemed amiss—articles were written, statements were issued about Steinman and the two other recipients, Bruce Beutler of the Scripps Research Institute and Jules Hoffmann of the French National Center for Scientific Research—until a few hours later, when news of Steinman’s death surfaced. The prize rules state that it cannot be given posthumously, but if a laureate dies between the October announcement and the award ceremony in December, he or she can remain on the list. This odd timing threw the committee into a closely followed deliberation before it announced, late in the day, that he would remain a prize recipient.
Just days after Steinman’s Nobel was announced and news of his death hit the media, pancreatic cancer also claimed the life of Apple’s cofounder and CEO, Steve Jobs. Jobs, ill with a rare, slower-growing form of the disease—a neuroendocrine tumor—lived for eight years after his diagnosis, more of an average survival time for a patient with his form of the disease. Steinman’s survival, though, far surpassed what was expected. “There’s no question something extended his life,” Schlesinger says.
Now researchers are working to figure out what it was. In early 2012 Baylor will be dedicating the Ralph Steinman Center for Cancer Vaccines, and Palucka is developing a clinical trial to treat pancreatic cancer patients with the same vaccine that she helped create for Steinman. At Argos, Nicolette is pursuing their kidney cancer vaccine full steam ahead: “There’s a sense of duty to Ralph to see this through.” This month they plan to launch a phase III clinical trial of the renal cancer vaccine Steinman tried.
For her part, Schlesinger believes her colleagues’ interventions made a contribution in the end. “The scientific message is: immunity makes a difference,” she says. But the final lesson is one Steinman liked to preach. “He used to tell people, ‘There are so many other things left to discover,’” she recalls. “And there are.”
NATHANIEL RICH
Can a Jellyfish Unlock the Secret of Immortality?
FROM The New York Times Magazine
AFTER MORE THAN 4,000 years—almost since the dawn of recorded time, when Utnapishtim told Gilgamesh that the secret to immortality lay in a coral found on the ocean floor—man finally discovered eternal life in 1988. He found it, in fact, on the ocean floor. The discovery was made unwittingly by Christian Sommer, a German marine-biology student in his early twenties. He was spending the summer in Rapallo, a small city on the Italian Riviera, where exactly one century earlier Friedrich Nietzsche conceived Thus Spoke Zarathustra: “Everything goes, everything comes back; eternally rolls the wheel of being. Everything dies, everything blossoms again . . .”
Sommer was conducting research on hydrozoans, small invertebrates that, depending on their stage in the life cycle, resemble either a jellyfish or a soft coral. Every morning, Sommer went snorkeling in the turquoise water off the cliffs of Portofino. He scanned the ocean floor for hydrozoans, gathering them with plankton nets. Among the hundreds of organisms he collected was a tiny, relatively obscure species known to biologists as Turritopsis dohrnii. Today it is more commonly known as the immortal jellyfish.
Sommer kept his hydrozoans in petri dishes and observed their reproduction habits. After several days he noticed that his Turritopsis dohrnii was behaving in a very peculiar manner, for which he could hypothesize no earthly explanation. Plainly speaking, it refused to die. It appeared to age in reverse, growing younger and younger until it reached its earliest stage of development, at which point it began its life cycle anew.
Sommer was baffled by this development but didn’t immediately grasp its significance. (It was nearly a decade before the word “immortal” was first used to describe the species.) But several biologists in Genoa, fascinated by Sommer’s finding, continued to study the species, and in 1996 they published a paper called “Reversing the Life Cycle.” The scientists described how the species—at any stage of its development—could transform itself back to a polyp, the organism’s earliest stage of life, “thus escaping death and achieving potential immortality.” This finding appeared to debunk the most fundamental law of the natural world—you are born, and then you die.
One of the paper’s authors, Ferdinando Boero, likened the Turritopsis to a butterfly that, instead of dying, turns back into a caterpillar. Another metaphor is a chicken that transforms into an egg, which gives birth to another chicken. The anthropomorphic analogy is that of an old man who grows younger and younger until he is again a fetus. For this reason Turritopsis dohrnii is often referred to as the Benjamin Button jellyfish.
Yet the publication of “Reversing the Life Cycle” barely registered outside the academic world. You might expect that, having learned of the existence of immortal life, man would dedicate colossal resources to learning how the immortal jellyfish performs its trick. You might expect that biotech multinationals would vie to copyright its genome; that a vast coalition of research scientists would seek to determine the mechanisms by which its cells aged in reverse; that pharmaceutical firms would try to appropriate its lessons for the purposes of human medicine; that governments would broker international accords to govern the future use of rejuvenating technology. But
none of this happened.
Some progress has been made, however, in the quarter century since Christian Sommer’s discovery. We now know, for instance, that the rejuvenation of Turritopsis dohrnii and some other members of the genus is caused by environmental stress or physical assault. We know that during rejuvenation it undergoes cellular transdifferentiation, an unusual process by which one type of cell is converted into another—a skin cell into a nerve cell, for instance. (The same process occurs in human stem cells.) We also know that, in recent decades, the immortal jellyfish has rapidly spread throughout the world’s oceans in what Maria Pia Miglietta, a biology professor at Notre Dame, calls “a silent invasion.” The jellyfish has been “hitchhiking” on cargo ships that use seawater for ballast. Turritopsis has now been observed not only in the Mediterranean but also off the coasts of Panama, Spain, Florida, and Japan. The jellyfish seems able to survive, and proliferate, in every ocean in the world. It is possible to imagine a distant future in which most other species of life are extinct but the ocean consists overwhelmingly of immortal jellyfish, a great gelatin consciousness everlasting.
But we still don’t understand how it ages in reverse. There are several reasons for our ignorance, all of them maddeningly unsatisfying. There are, to begin with, very few specialists in the world committed to conducting the necessary experiments. “Finding really good hydroid experts is very difficult,” says James Carlton, a professor of marine sciences at Williams College and the director of the Williams-Mystic Maritime Studies Program. “You’re lucky to have one or two people in a country.” He cited this as an example of a phenomenon he calls the Small’s Rule: small-bodied organisms are poorly studied relative to larger-bodied organisms. There are significantly more crab experts, for instance, than hydroid experts.
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