by Sam Kean
“These are the genes in this particular tumor that have been hit,” Newman says in a Yorkshire accent that emphasizes the t at the end of the word hit in a quietly violent way. “And that’s just one type of thing that’s going on. Chromosomes get gained or lost in cancer. This one has gained that one, that one, that one, that one,” he taps the page over and over. “And then there are structural rearrangements where little bits of genome get switched around.” He points to the arcs sweeping across the page. “There are no clearly defined rules.”
It’s not like you don’t have cancer and then one day you just do. Cancer—or, really, cancers, because cancer is not a single disease—happens when glitches in genes cause cells to grow out of control until they overtake the body, like a kudzu plant. Genes develop glitches all the time: there are roughly 20,000 genes in the human body, any of which can get misspelled or chopped up. Bits can be inserted or deleted. Whole copies of genes can appear and disappear, or combine to form mutants. The circle plot Newman has shown me is not even the worst the body can do. He whips out another one, a snarl of lines and blocks and colors. This one would not make a good tattoo.
“As a tumor becomes cancerous and grows, it can accumulate many thousands of genetic mutations. When we do whole genome sequencing, we see all of them,” Newman says. To whittle down the complexity, he applies algorithms that pop out gene mutations most likely to be cancer-related, based on a database of all the mutations researchers have already found. Then, a genome analyst manually determines whether each specific change the algorithm found seems likely to cause problems. Finally, the department brings its list of potentially important changes to a committee of St. Jude’s top scientists to discuss and assign a triage score. The mutations that seem most likely to be important get investigated first.
It took 13 years and cost $2.7 billion to sequence the first genome, which was completed in 2003. Today, it costs $1,000 and takes less than a week. Over the last two decades, as researchers like Newman have uncovered more and more of the individual genetic malfunctions that cause cancer, teams of researchers have begun to tinker with those mutations, trying to reverse the chaos they cause. (The first big success in precision medicine was Gleevec, a drug that treats leukemias that are positive for a common structural rearrangement called the Philadelphia chromosome. Its launch in 2001 was revolutionary.) Today, there are 11 genes that can be targeted with hyperspecific cancer therapies, and at least 30 more being studied. At Memorial Sloan Kettering Cancer Center in New York City, 30 to 40 percent of incoming patients now qualify for precision medicine studies.
Charles Mullighan, a tall, serious Australian who also works at St. Jude, is perhaps the ideal person to illustrate how difficult it will be to cure cancer using precision medicine. After patients’ cancer cells are sequenced, and the wonky mutations identified, Mullighan’s lab replicates those mutations in mice, then calls St. Jude’s chemical library to track down molecules—some of them approved medicines from all over the world, others compounds that can illuminate the biology of tumors—to see if any might help.
If Mullighan is lucky, one of the compounds he finds will benefit the mice, and he’ll have the opportunity to test it in humans. Then he’ll hope there are no unexpected side effects, and that the cancer won’t develop resistance, which it often does when you futz with genetics. There are about 20 subtypes of the leukemia Mullighan studies, and that leukemia is one of a hundred different subtypes of cancer. This is the kind of precision required in precision cancer treatment—even if Mullighan succeeds in identifying a treatment that works as well as Gleevec, with the help of an entire, well-funded hospital, it still will work for only a tiny proportion of patients.
Cancer is not an ordinary disease. Cancer is the disease—a phenomenon that contains the whole of genetics and biology and human life in a single cell. It will take an army of researchers to defeat it.
Luckily, we’ve got one.
Interlude
“I used to do this job out in L. A.,” says the attendant at the Hertz counter at Houston’s George Bush Intercontinental Airport. “There, everyone is going on vacation. They’re going to the beach or Disneyland or Hollywood or wherever.
“Because of MD Anderson, I see more cancer patients here. They’re so skinny. When they come through this counter, they’re leaning on someone’s arm. They can’t drive themselves. You think, there is no way this person will survive. And then they’re back in three weeks, and in six months, and a year. I’m sure I miss some, who don’t come through anymore because they’ve died. But the rest? They come back.”
II. Checkpoint Inhibitor Therapy—Or, You Have the Power Within You!
On a bookshelf in Jim Allison’s office at MD Anderson Cancer Center in Houston (and on the floor surrounding it) are so many awards that some still sit in the boxes they came in. The Lasker-DeBakey Clinical Medical Research Award looks like the Winged Victory statue in the Louvre. The Breakthrough Prize in Life Sciences, whose benefactors include Sergey Brin, Anne Wojcicki, and Mark Zuckerberg, came with $3 million.
“I gotta tidy that up sometime,” Allison says.
Allison has just returned to the office from back surgery that fused his L3, L4, and L5 vertebrae, which has slightly diminished his Texas rambunctiousness. Even on painkillers, though, he can explain the work that many of his contemporaries believe will earn him the Nobel Prize: he figured out how to turn the immune system against tumors.
Allison is a basic scientist. He has a Ph.D., rather than an M.D., and works primarily with cells and molecules rather than patients. When T-cells, the most powerful “killer cells” in the immune system, became better understood in the late 1960s, Allison became fascinated with them. He wanted to know how it was possible that a cell roaming around your body knew to kill infected cells but not healthy ones. In the mid-1990s, both Allison’s lab and the lab of Jeffrey Bluestone at the University of Chicago noticed that a molecule called CTLA-4 acted as a brake on T-cells, preventing them from wildly attacking the body’s own cells, as they do in autoimmune diseases.
Allison’s mother died of lymphoma when he was a child, and he has since lost two uncles and a brother to the disease. “Every time I found something new about how the immune system works, I would think, I wonder how this works on cancer?” he says. When the scientific world discovered that CTLA-4 was a brake, Allison alone wondered if it might be important in cancer treatment. He launched an experiment to see if blocking CTLA-4 would allow the immune system to attack cancer tumors in mice. Not only did the mice’s tumors disappear, the mice were thereafter immune to cancer of the same type.
Ipilimumab (“ipi” for short) was the name a small drug company called Medarex gave the compound it created to shut off CTLA-4 in humans. Early trials of the drug, designed just to show whether ipi was safe, succeeded so wildly that Bristol-Myers Squibb bought Medarex for $2.4 billion. Ipilimumab (now marketed as Yervoy) became the first “checkpoint inhibitor”: it blocks one of the brakes, or checkpoints, the immune system has in place to prevent it from attacking healthy cells. Without the brakes the immune system can suddenly, incredibly, recognize cancer as the enemy.
“You see the picture of that woman over there?” Allison points over at his desk. Past his lumbar-support chair, the desk is covered in papers and awards and knickknacks and frames, including one containing a black card with the words “Never never never give up” printed on it. Finally, the photo reveals itself, on a little piece of blue card stock.
“That’s the first patient I met,” Allison says. “She was about twenty-four years old. She had metastatic melanoma. It was in her brain, her lungs, her liver. She had failed everything. She had just graduated from college, just gotten married. They gave her a month.”
The woman, Sharon Belvin, enrolled in a phase-two trial of ipilimumab at Memorial Sloan Kettering, where Allison worked at the time. Today, Belvin is thirty-five, cancer-free, and the mother of two children. When Allison won the Lasker prize, in 2015, the commi
ttee flew Belvin to New York City with her husband and her parents to see him receive it. “She picked me up and started squeezing me,” Allison says. “I walked back to my lab and thought, Wow, I cure mice of tumors and all they do is bite me.” He adds, dryly, “Of course, we gave them the tumors in the first place.”
After ipi, Allison could have taken a break and waited for his Nobel, driving his Porsche Boxster with the license plate CTLA-4 around Houston and playing the occasional harmonica gig. (Allison, who grew up in rural Texas, has played since he was a teenager and once performed “Blue Eyes Crying in the Rain” onstage with Willie Nelson.) Instead, his focus has become one of two serious problems with immunotherapy: it only works for some people.
So far, the beneficiaries of immune checkpoint therapy appear to be those with cancer that develops after repeated genetic mutations—metastatic melanoma, non-small-cell lung cancer, and bladder cancer, for example. These are cancers that often result from bad habits like smoking and sun exposure. But even within these types of cancer, immune checkpoint therapies improve long-term survival in only about 20 to 25 percent of patients. In the rest, the treatment fails, and researchers have no idea why.
Lately, Allison considers immune checkpoint therapy a “platform”—a menu of treatments that can be amended and combined to increase the percentage of people for whom it works. A newer drug called Keytruda that acts on a different immune checkpoint, PD-1, knocked former president Jimmy Carter’s metastatic melanoma into remission in 2015. Recent trials that blocked both PD-1 and CTLA-4 in combination improved long-term survival in 60 percent of melanoma patients. Now, doctors are combining checkpoint therapies with precision cancer drugs, or with radiation, or with chemotherapy. Allison refers to this as “one from column A, and one from column B.”
The thing about checkpoint inhibitor therapy that is so exciting—despite the circumscribed group of patients for whom it works, and despite sometimes mortal side effects from the immune system going buck-wild once the brakes come off—is the length of time it can potentially give people. Before therapies that exploited the immune system, response rates were measured in a few extra months of life. Checkpoint inhibitor therapy helps extremely sick people live for years. So what if it doesn’t work for everyone? Every cancer patient you can add to the success pile is essentially cured.
Jennifer Wargo is another researcher at MD Anderson who is trying to predict who will respond to checkpoint inhibitor therapy and who will not. Originally a nurse, Wargo got so interested in biology that she went back to school for a bachelor’s degree, then a medical degree, and then a surgical residency at Harvard. It was during her first faculty position, also at Harvard, around 2008, that she started to wonder how the microbiome—the bacteria that live in the human body, of which there are roughly 40 trillion in the average 155-pound man—might affect cancer treatment. Wargo was investigating the bacteria that live near the site of pancreatic cancer—in and around the tumor. Could you target those bacteria with drugs and make the cancer recede more quickly?
In the early 2010s, research about the microbiome in the human gut—the bacteria in humans’ stomachs and intestines that appear to affect immune function, gene expression, and mood, among other things—gained traction in journals. Before long, two separate researchers had shown that you could change a mouse’s response to immune checkpoint inhibitor therapy by giving him certain kinds of bacteria. Wargo added the microbiome to her slate of experiments. Along with her team, she collected gut microbiome samples from more than 300 cancer patients who then went on to receive checkpoint inhibitors as treatment. The results were, Wargo says, “night and day.” People who had a higher diversity of gut bacteria had a stronger response to checkpoint inhibitor therapy.
Now, Wargo is transplanting stool samples from patients into germ-free mice with melanoma, to see if she can predict whether the mice will mimic the treatment responses of the people whose bacteria they received. “Can we change the gut microbiome to enhance responses to therapy . . . or even prevent cancer altogether?” she says. “Ah god, that would be the holy grail, wouldn’t it?” she whispers, as if not to invite bad luck. “It’s gonna take a lot of work to get there, but I think the answer is gonna be yes.”
Immunotherapies do have one other problem worth worrying about, one that underlies the most frustrating experience of having cancer. When a patient is diagnosed, the first therapy is still one of the standards: surgery, radiation, or chemotherapy. Cut, burn, or poison, as the doctors say. Doctors can’t use promising immunotherapies as first-line treatments yet because immunotherapies are still dangerous: No one knows what will happen long-term if you shut off the immune system’s brakes. Does a patient survive cancer just to develop another terrible disease, like amyotrophic lateral sclerosis (ALS), in 15 years?
Interlude
“Just to play devil’s advocate,” says a woman at a margarita bar and restaurant in Santa Fe, New Mexico. “Don’t you think the cure exists somewhere already and the medical industrial complex is hiding it? People stand to lose billions of dollars. Don’t you think they want to keep that money?”
I have been talking to this woman for 20 minutes. She is familiar with cancer. She works with natural cures, is a big fan of neuroscience, and knows some of the prominent names in medical research. I tell her that the conspiracy theory she is referencing—that the government or pharmaceutical industry is hiding the cure for cancer—can’t be true. Of course it’s hard to believe that Richard Nixon initiated the war on cancer in 1971 and the disease still kills 595,690 people a year. And that the most brilliant minds of our time have turned HIV into a chronic disease but cancer continues relatively unchecked. And yet I’ve talked to 35 researchers and policymakers and visited seven cancer centers and I haven’t seen a shred of evidence that doctors who treat very sick people—and whose job it is, sometimes, to tell people that they will die—aren’t trying with their very souls to succeed at their jobs.
“It’s just that it’s hard,” I say.
The woman huffs. Someone more interesting is sitting on the other side of her. And that’s the end of that.
III. CAR-T Cells—Or, Tiny Machines
On a shelf in Crystal Mackall’s office at Stanford University in Palo Alto, California, catty-corner to a window that looks out on a lovely California scrub scape, is a teddy bear that once belonged to a boy named Sam.* Sam, who Mackall treated at the National Cancer Institute more than 10 years ago, had Ewing’s sarcoma, a rare cancer that usually affects children and grows in or around bones.
Mackall is a pediatric oncologist with a dark blond bob and a wry, take-no-prisoners sense of humor. She has worked on cancer since the 1980s, so she has met a lot of very, very sick children. The way Mackall tells the story of Sam, like she’s taking a shot of foul-tasting medicine, you can see the distance she’s had to put between her emotions and her work. “We lost Sam. He was ten,” she says. “We gave him immunotherapy and it didn’t work.”
With that, Mackall moves on to the story of a girl named Lisa, who is pictured in a photo not far from the bear. Lisa had the same illness as Sam around the same time, but her therapy did work. Lisa’s story lasts more than a minute, with Mackall practically cheering at the end. “So she remained fertile and that’s her little boy!” she yells, gesturing toward Lisa’s photo. Mackall smiles the pained, confused smile of someone who has inexplicably survived a car crash. “You have your ups and your downs,” she says.
Overall, children’s cancer has been one of the great success stories in cancer treatment. In the 1970s, dramatic advances in chemotherapy put most patients with certain types of leukemia (particularly acute lymphoblastic leukemia in B-cells, otherwise known as B-ALL) into remission. Today, 84 percent of children who get ALL can be cured. But then treatment stalled. “We have made steady progress, by all accounts,” says Mackall. “But it’s been largely incremental. And there’ve been these plateaus that have just driven us crazy.”
In those unfortunate
few children who relapsed or didn’t respond to the chemo, or who got a different variety of cancer, like Ewing’s sarcoma, there were few treatments left to try. Mackall’s patients came to her after having had surgery and then chemotherapy once, twice, three times. “You can just see, they’re beat-up. They’re making it, but all they do is get their treatments,” she says. “They didn’t have enough energy to do anything else.” And then, if they lasted long enough, they got into a trial.
There are several ways to turn the immune system against cancer. Checkpoint inhibitor therapy is one of them. But it doesn’t work in all patients, especially children, whose cancers generally do not have the vast numbers of mutations needed to attract the attention of a newly brake-free immune system. For a long, dark time, immunotherapists would try other sorts of techniques to get the immune system to respond in these patients, and the patients would die anyway, like Sam did. The treatments were toxic or they damaged the brain or they just didn’t work. The doctors would recommend hospice. Hospice. Hospice.
And then all the research began to pay off. In August 2010, a retired correctional officer named Bill Ludwig walked into the Hospital of the University of Pennsylvania to try a new therapy developed by a researcher named Carl June. Ludwig had chronic lymphocytic leukemia (CLL), another cancer that affects B-cells. Multiple rounds of chemotherapy had failed to cure it, and he didn’t qualify for a bone marrow transplant. June’s idea, which was so risky that the National Institutes of Health had turned down several grant applications to fund it, was the only option Ludwig had. June had only enough money to try it in three patients. Ludwig went first.
To understand how June’s therapy works, consider the T-cells that Jim Allison found fascinating. They’re cells that kill other cells, but they don’t kill you because they have a built-in targeting mechanism. Each person has millions of T-cells, and each one of those T-cells matches a single virus, like a lock and a key. If a virus enters the body, its own personal T-cell key will find and destroy it, then copy and copy and copy itself until the virus succumbs. “I liken it to a bloodhound,” says Mackall. “What the marker says to the T-cell is: Anything that has this thing on it, kill it.”