programs to study “exceptional responders”: those rare

NAUTIL.US | TEXT SETS programs to study “exceptional responders”: those rare cancer patients who do well while nobody else does. Cancer is a personal disease, Solit explains. Each tumor constitutes its own world of defective genes and proteins. By studying the genetic quirks of exception- al responders, physicians can systematically identify weaknesses in cancer subtypes and blast them with drugs that target their unique vulnerabilities. “It’s a testament to how much has been learned about the genome in the past 30 years,” Solit says. “We’ ve always wanted to find out why some individuals respond so well. Now we have the capacity. It’s going to really change the way we treat patients.” UNLIKELY CASES HAVE AN eminent history in medi- cine. The modern science of the mind owes a lot to the freakish accident suffered by Phineas Gage, a 19th century railroad construction foreman whose job involved packing down explosive powder with a three-and-a-half-foot-long iron tamping rod. On Sept. 13, 1848, the powder exploded in his face, blasting the rod up through his chin and out the back of his head. Against all odds, he survived. But his personality was transformed. The formerly shrewd and patient Gage became obnoxious and unreliable. An observant doctor named John Martyn Harlow who cared for Gage proposed that his personality change was due to the destruction of the frontal lobe of the left side of the brain. Gage’s unlikely transfor- mation revealed a universal truth about brains, that particular parts—the frontal lobes—are required for self-control. The strange case of Phineas Gage is still mentioned in neuroscience textbooks. Rare events can also lead to new cures. As the story goes, English physician Edward Jenner’s observations of an 18th century milkmaid who caught cowpox and thereby became immune to smallpox paved the way for the fi vaccines. New ideas for curing HIV are emerg- ing from the famously unlucky lucky case of the “Berlin patient.” Timothy Ray Brown, who was HIV positive, developed blood cancer leukemia in 2006. His chemo- therapy and radiation treatments wiped out the cells of his immune system, where the virus is believed to hide. He then got a bone marrow transplant from one of those rare people with a gene mutation that makes them resistant to HIV. Today, Brown still has no sign 37 of HIV in his body, and his case has inspired a study to genetically engineer HIV-positive patients’ cells to resist the virus. In the past, cancer researchers weren’t able to capitalize on their unexpected outlier successes. Not enough was known about the biology of cancer, and the right tools hadn’t been invented. “Even if someone had a complete remission, you had no way to figure out why,” says James Doroshow, director of the Division of Cancer Treatment and Diagnosis of the National Can- cer Institute (NCI). That changed in the 2000s, when it became possible to analyze the genetics of cancer tumors for clues. The first major success came with studies of the drug gefitinib in non-small-cell lung cancer (the most common kind). Gefitinib helped less than 20 percent of the people who took it, but a few outliers had dra- matic, rapid recoveries. In 2004, two Harvard groups found that the responders had mutations in the epi- dermal growth factor receptor (EGFR) gene. EGFR 1s one of many genes that regulates how cells grow and when they die, and the mutation basically forced it to pump out two or three times as much growth signal as it should, fueling the cancer. Gefitinib dialed down the signal. A clinical trial later proved that the drug keeps tumors at bay for more than nine months in people with certain EGFR mutations. More insights gleaned from extraordinary respond- ers soon followed. One melanoma patient in a study of 22 people taking sorafenib saw his tumor shrink quick- ly, a response due to a mutation in the gene KIT, which regulates cell growth, division and survival. People with certain kinds of melanoma, such as the type that grows on mucus membranes, now routinely get tested for this mutation. The drug helps about 40 percent of those with the mutation—an impressive advance in a cancer that once had no effective treatment. In these studies, investigators had to make educat- ed guesses about where in the genome to look for the culprit mutations. It was the keys-under-the-lamppost phenomenon: They could only examine genes they already suspected were involved in the cancer. But as the speed and efficiency of DNA sequencing skyrocket- ed, and its price plummeted, it started to look reason- able to sequence the whole tumor genome to cast the widest possible net. By 2010, when the bladder cancer HOUSE_OVERSIGHT_015497