Deathstalker scorpion Christopher Griffith
Because it’s so late on a Monday afternoon, there is a listless vibe inside the University of Washington lecture hall where Jim Olson is about to speak. The audience consists of a few dozen grad students struggling with end-of-day fatigue. They scarf down free chocolate-chunk cookies as they prepare to take notes, but sugar can sharpen mental alertness only so much. The talk they’ve come to hear, part of a biweekly series on current topics in neuroscience, doesn’t exactly seem like edge-of-your-seat material.
Olson’s first slide wakes them up. It is a pixelated photograph of an adorable 6-year-old boy named Hayden Strum, who sports a white Quiksilver T-shirt and a pirate-style eye patch. Hayden, who suffered from a pernicious brain tumor, came to Olson in 1995, back when Olson was just starting his career as a pediatric oncologist and cancer researcher. For four years, the doctor treated Hayden with successive rounds of chemotherapy and major surgeries, but nothing could save the boy’s life. Olson tells the audience that while sitting in the back row at Hayden’s memorial service, listening to the speakers express their pain, he had an epiphany about his scientific priorities.
“I decided that I would never design an experiment just to get grants or publications or promotions,” says the 51-year-old Olson, whose ruddy complexion and Midwestern geniality give him the aura of a hip youth minister. “Every experiment I ever did was going to be to make sure that other boys and girls didn’t have to go through what Hayden had gone through.” Having been caught off guard by the emotional wallop of his opening story, Olson’s audience stays rapt as he goes on to describe a decade-long quest to solve one of the most vexing problems in oncology: the fact that a tumor’s precise boundaries are nearly impossible to define during surgery. A preoperative MRI provides only a rough guide to a tumor’s fuzzy edges; the scans often miss slivers of cancer that seamlessly blend into the surrounding tissue. Surgeons often face a brutal catch-22: Either cut out any suspicious tissue, an approach that can lead to debilitating side effects, or risk leaving behind malignant cells that will eventually kill the patient.
Olson tells the students that he finally has a solution. His laboratory at the renowned Fred Hutchinson Cancer Research Center, located just down the road by Seattle’s Lake Union, has developed a compound that appears to pinpoint all of the malignant cells in a patient’s body. It gives those cells a bright fluorescent sheen, so that surgeons can easily spot them in the operating room. Olson calls the product Tumor Paint, and it comes with a surprising twist: The compound’s main ingredient is a molecule that is found in the stinger of Leiurus quinquestriatus, a potent little animal more popularly known as the deathstalker scorpion.
A scorpion-venom concoction that makes tumors glow sounds too outlandish to be true. At least that’s what the grant-making organizations thought.
A scorpion-venom concoction that makes tumors glow sounds almost too outlandish to be true. In fact, Olson explains, that’s what troubled the big grant-making organizations when he came to them for funding. But when those organizations dismissed his ideas as too bizarre, Olson started accepting donations from individuals—particularly the families of current and former patients—quickly raising $5 million for his research. It was a bold and unprecedented tactic: Though patients and their families are often asked to donate to foundations with broad goals, Olson raised money for one specific, untested technology—a much riskier gamble. But thanks to his efforts, Olson’s fluorescent scorpion toxin is now in Phase I clinical trials, an impressive accomplishment for a compound with such a peculiar lineage. The University of Washington students are clearly awed by the work.
This is hardly the first crowd that Olson has dazzled with the story of Tumor Paint. For the past few years, he has been delivering his pitch from coast to coast, often at buzzy general-interest conferences such as PopTech and South by Southwest. These poignant presentations and the attendant media coverage have earned Olson a small measure of fame—enough, for example, so that he was featured in a short documentary that screened at the 2013 Sundance Film Festival. They’ve also earned him additional funding: Olson always ends his talks by urging his audience to visit his crowdfunding platform, Project Violet, where they can make direct donations to his lab.
Both his idea and his approach to funding it make Olson something of a maverick in the field of cancer research. There are critics who worry that the oncologist might be offering more hope than he can deliver—particularly to the desperate loved ones of his patients. But Olson’s mission is to prevent more kids from suffering Hayden Strum’s fate, and to do that, he says, he must rely on families who possess intimate knowledge of what’s at stake. “Without them,” he says, “Tumor Paint wouldn’t exist. Simple as that.”
Jim Olson was just four when he discovered the book that made him want to be a doctor. It was a vintage medical encyclopedia that he had pulled off the shelves of his family’s home in Escanaba, a town on the southern coast of Michigan’s Upper Peninsula. In the center of the book was a clear plastic page embossed with a portrait of a human body. The next page had a depiction of the body with its skin stripped away, followed by a drawing of the circulatory system and then the vital organs. Enthralled by the act of flipping through the human anatomy layer by layer, Olson knew that he wanted to grow up to be one of those wise men with stethoscopes who get to tinker with muscle, blood, and bone.
A career in medicine was an ambitious goal for Olson given his family’s circumstances. His father, an electrician by trade, had a serious drinking problem at the time that wreaked havoc on Olson’s parents’ marriage. After they divorced when Olson was 7, his mother supported her two children with a minimum-wage clerical job at an insurance company; the kids often subsisted on black-bear roasts provided by their uncles, who were avid hunters. When Olson matriculated at Western Michigan University in the fall of 1981, he became the first member of his family to attend college.
Olson excelled at Western Michigan, graduating from the school’s honors program in three years. For most of his college career, his long-term plan was to earn a medical degree and then return to Escanaba to become a family doctor. But late in his senior year he decided that he didn’t want to spend his life sewing sutures in his provincial hometown. He instead opted to enroll in the University of Michigan’s prestigious MD-PhD program, which would prepare him to become a scientist as well as a clinician.
Jim Olson shows off his tattoo, which represents the knot of disulfide bonds at the center of the chlorotoxin molecule. John Clark
Toward the end of the MD portion of the program, Olson was the med student assigned to the case of a 7-year-old girl with a rare and devastating neurological disorder. The girl was losing cranial nerve functions every day, and it was clear that she would soon die unless she was connected to a ventilator—something her parents opted not to do. On the day the girl died, Olson walked from the hospital to the university’s arboretum, where he intended to mourn privately amid the trees. He was surprised to discover that he felt little sorrow.
“I was remarkably high-spirited,” Olson recalls. “And that was really odd to me, because this was the first time I’d had a child die on me.” While meditating by the Huron River, Olson realized how much he had been moved by something the girl’s parents had said to him a few hours earlier. They told Olson that the way he had cared for their daughter helped them see that a person needn’t live until 80 for their life to have been a triumph. Recognizing his ability to deal with despair, Olson decided that he was meant to become a pediatric oncologist, a specialty that rewards a philosophical approach to tragedy.
Olson would end up pursuing that specialty in the Pacific Northwest, where he moved in 1991 to take a residency, and later a fellowship, at Seattle Children’s Hospital. Despite his high tolerance for heartbreak, though, Olson was battered by his first full year of caring for dying kids. Pent-up grief would overwhelm him at odd moments; he once turned into a blubbering mess upon discovering that the tomato plants in his front yard were afflicted with blight. “I can’t even take care of a plant!” Olson thought as he kneeled in the dirt by his discolored tomatoes.
In 2000 Olson established his own lab at Fred Hutchinson, where he could channel his emotions into finding ways to increase his patients’ odds of survival. Initially the lab focused on conventional projects, such as investigating whether existing drugs could inhibit cancer cell growth. But its research took a novel turn in May 2004, after Olson and several other Seattle Children’s oncologists met to review the case of a shy and studious 17-year-old girl who had recently undergone brain tumor surgery. When the doctors examined the girl’s MRI scans, they made a depressing discovery: Despite the surgical team’s painstaking work, a thumb-sized chunk of cancer cells remained inside her head.
The realization was disheartening but not unexpected. “You know, a tumor doesn’t have a big sign that says ‘Here I Am,’” says Steven Rosenfeld, director of the Brain Tumor Research Center of Excellence at the Cleveland Clinic. “An MRI can be helpful, but it doesn’t identify all of the microscopic deposits and nests where the tumor occurs.” Neurosurgeries are particularly tricky because the brain has a gelatinous consistency—surgeons compare it to a wobbly slab of Jell-O. Poking and prodding an exposed brain with sharp instruments alters its shape, thereby rendering MRI images useless as guides.
As soon as the meeting adjourned, Olson was beckoned aside by Richard Ellenbogen, the neurosurgeon who had performed the girl’s operation. He was visibly frustrated by the outcome. “You’ve got to find some way to help us see these cancers better,” he implored Olson.
Olson instantly thought back to his University of Michigan dissertation. The paper was about the use of a radioactive isotope in PET scans that can diagnose cancers. The isotope is employed as a tracer that will emit detectable gamma rays upon reaching its target within the body, helping determine if a certain type of cancer is present. Olson now wondered whether he could devise a similar technique to illuminate cancers with simple beams of light, so that malignant cells would shine not just on PET scans but also during actual surgeries.
Olson thought he could accomplish this feat by modifying a molecule known to bind specifically to cancer cells. If he could attach a fluorescent dye to such a molecule, maybe he could make the tumors glow a brilliant blue or green when viewed through a near-infrared camera positioned next to the operating table. Surgeons would then have no problem seeing exactly where a tumor began and ended.
Since he needed someone to spearhead the search for an appropriate molecule, Olson borrowed one of Ellenbogen’s top neurosurgery residents, a meticulous young man named Patrik Gabikian. Olson put Gabikian to work as a sleuth, asking him to comb through all existing databases in the hopes of unearthing a molecule that would latch onto tumor cells while ignoring the healthy cells around them. Every night, Gabikian would hand his new boss a list of candidates that he’d discovered that day. And for six exasperating weeks, Olson would reject each molecule for any number of reasons—a structure that made it too difficult to attach a dye to, for example, or the likelihood of adverse side effects elsewhere in the body.
Olson’s interest was finally piqued by one of Gabikian’s more peculiar suggestions: chlorotoxin, a substance found in the venom of the deathstalker scorpion. Despite its unusual background, the molecule was already a budding star in the biotech world.
Ancient practitioners of medicine were well aware that scorpion venom could heal as well as harm. In imperial China, for example, the cloudy fluid was used to treat ailments ranging from mumps to tetanus. And in certain rural corners of India, whole scorpions were dipped in mustard oil and then rubbed on arthritic joints. Scorpion venom has more recently become an object of fascination for developers of pesticides, who dream of protecting crops using the neurotoxins that scorpions employ against locusts and beetles.
Today pharmaceutical companies regularly obtain venom for commercial use by milking deathstalkers—that is, jolting the yellow arachnids with electricity, then collecting the droplets that dribble forth from their tails. Courage is an essential trait for the technicians who handle this sort of work, for the deathstalker is among the most dangerous scorpions in the world: In certain instances, L. quinquestriatus venom can cause cardiac arrest.
Scorpion venoms are cocktails of numerous individual toxins, which attack different targets within a victim’s body. The initial American research on the deathstalker’s venom focused on these toxins’ ability to block electrical signals generated by the movement of sodium ions. Then, in 1993, a team at Harvard Medical School identified a new L. quinquestriatus toxin that appeared to block the channels that cells use to pass chloride ions across their membranes. The researchers noted that this molecule, which they dubbed chlorotoxin, consists of a short chain of amino acids—a peptide, in biochemical parlance. At the center of this particular 36-amino-acid peptide is a tightly packed structure consisting of four disulfide bonds, which gives the molecule a knot at its core. Despite its ominous name, pure chlorotoxin is harmless to humans; its sole evolutionary purpose seems to be to paralyze the muscles of the cockroaches that the deathstalker likes to eat.
In 1994 the Harvard researchers’ paper in the American Journal of Physiology caught the eye of Nicole Ullrich, an MD-PhD student at the University of Alabama at Birmingham. (She is now a neuro-oncologist at the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center.) Ullrich was investigating a nasty type of brain tumor called glioma, whose sufferers have a five-year survival rate of just 5 percent. Glioma cells move through the brain by contorting their shapes, a feat they pull off by secreting chloride ions—a bit like plump sausages becoming slinkier as their salty juices cook away. Ullrich hypothesized that the tumors could be held in check if there were a drug capable of blocking their ability to “sweat” chloride. Chlorotoxin promised to do just that.
When she injected chlorotoxin into the brains of mice with gliomas, Ullrich found that the peptide would bind only to the cancer cells; the molecule wanted nothing to do with the normal cells adjacent to the tumors. When she shared this serendipitous behavior with her lab’s director, a neurobiologist named Harald Sontheimer, the two began to dream big about chlorotoxin’s potential. “When a patient comes in and they’re symptomatic for glioma, the invasion of the tumor to other parts of the brain has already begun,” Sontheimer says. “So instead of using this as a drug just to inhibit that invasion process, we wanted to put a deadly payload on it and use it for the targeted delivery of cellular poison.” The hope was that this new form of targeted chemotherapy would cause no side effects, since the chlorotoxin wouldn’t accidentally transport any of that cancer-killing poison into healthy cells.
By the time Jim Olson and Patrik Gabikian stumbled upon chlorotoxin in 2004, a decade after Ullrich’s initial encounter with the peptide, Sontheimer’s chlorotoxin-based drug had completed Phase I clinical trials. Those trials yielded such promising results that Sontheimer’s biotech company, TransMolecular, was able to secure $33.2 million in venture capital as it prepared the drug for Phase II. Olson, by contrast, could only dream of such lavish funding as he began to design his initial chlorotoxin experiments. He had to bargain hard just to afford a few hundred milligrams of the peptide from an Israeli pharmaceutical company. Even after an intense round of negotiation, Olson had to pay $100,000 for his chlorotoxin.
But this big expenditure was justified by the experimental results. Olson and Gabikian found that the chlorotoxin didn’t attach just to brain tumors—it grabbed onto all sorts of cancers, from those that affect the skin to those that destroy the lungs. They also learned that the peptide could cross the barrier that protects the brain from toxins and other chemicals—a rare attribute for a molecule of its size, and one that Olson credits to the fact that scorpions have had millions of years to evolve methods to infiltrate their prey. This capability meant that the peptide could be administered intravenously rather than injected locally into the brain.
The most incredible revelation came when Olson began to inject fluorescent-tipped chlorotoxin into mice—the compound lit up cancer cells that no other technology could identify. In one instance, the chlorotoxin illuminated a clump of just 200 malignant cells that were burrowed deep within a wad of fat. “That was the point we learned that the technology was far more sensitive than an MRI,” Olson says. To advance his chlorotoxin research, Olson applied for grants from the National Cancer Institute and other eminent organizations. But not a single one agreed to back his cause. “The rejections were based on comments like ‘This is highly speculative’ or ‘This is highly ambitious,’ which is grant code for ‘They are proposing more than I think they can accomplish,’” Olson says.
But Olson had supreme confidence in chlorotoxin’s value. The series of rejections just led him to conclude that creative research such as his required creative funding.
Eleven-year-old Carson knows exactly what’s coming next, which is why he’s hunched over and retching on the edge of the exam table. His father, a brawny Navy sailor, tries to soothe the boy by tenderly rubbing his back. But the massage can’t stop the digestive spasms, the physical manifestation of Carson’s dread of the toxic chemicals that will soon be pumped into his body.
Olson places a wastepaper basket beneath the boy’s chin as he assures the father that this sort of Pavlovian response is common among chemotherapy patients. “There’s a story of a patient, 30 years later he walks into a restaurant and he sees the doctor who treated him,” Olson says. “He goes over to the doctor’s table to say hi, and as soon as he opens his mouth he vomits all over everything. The memory, it can really be that strong.”
The darkly comic anecdote eases the tension in the room, in part because it hints at the best possible outcome for Carson—one in which the blond and freckled preadolescent will reach a healthy middle age. That future is far from guaranteed, because Carson was born with neurofibromatosis, a condition that causes tumors to sprout all over his body. His latest cycle of chemo, intended to shrink a tumor that is pressing against his brain, commenced soon after doctors sliced a big growth off his right leg; when Carson’s nausea finally passes and he lies back down, his sweatpants ride up to reveal a canyonlike scar.
Olson is entirely calm as he prepares the boy for chemo, an attitude that never wavers during his harrowing daily rounds. A fourth grader who may not live to celebrate another birthday, a teenage girl whose gloomy prognosis has made her suicidal—none of these encounters erase Olson’s tranquil smile.
That steady bedside manner has always been much appreciated by the families of Olson’s patients, and they’ve long expressed their gratitude by supporting his research. Shortly after Olson founded his Fred Hutchinson lab in 2000, for example, a few parents banded together to host chili cook-offs and golf tournaments to raise money for staff salaries. And so when they heard that none of his chlorotoxin grants came through, parents upped their fundraising efforts. “I embraced their generosity,” Olson says. He began to reach out to more families after the earliest group of donors assured him that they would go to any length “to make sure you have the funding you need when you have a good idea.”
Olson’s chlorotoxin pitch especially resonated with parents who had seen firsthand the limits of cancer surgery. Among them was Kris Forth, whose son, Brandon, had multiple surgeries to remove a tumor on his brain’s fourth ventricle. “There was always a piece of the cancer left inside him,” says Forth, who was by Brandon’s bedside when he died in March 2010 at the age of 11. “If Tumor Paint had been available then, it probably would have changed the outcome.” As part of her healing process, she opened a thrift store that has given tens of thousands of dollars to Olson’s lab; an informational poster about Tumor Paint hangs by the shop’s cash register.
The $5 million in crowdsourced donations that Olson eventually raised from thousands of donors was critical to his efforts to refine his cancer-seeking compound. After several years of fine-tuning, Tumor Paint started to show enough promise to attract funding from conventional channels. The National Cancer Institute chipped in a quarter-million dollars, a portion of which was used to launch a canine study at Washington State University; the veterinary surgeons there have been enthusiastic about the results. In 2010, Olson founded Blaze Bioscience, which has now raised $20 million, all through individuals. Blaze launched the first human clinical trial of Tumor Paint in December 2013; a second Phase I trial is slated to begin later this year.
Olson first showed me his one and only tattoo just days after he’d gotten it etched into his left shoulder. We were at the modernist lakeside home of his friend Anne Croco, an interior designer who is a key supporter of Olson’s lab. The two were discussing plans for a fund-raiser, to which Croco wanted to invite Pearl Jam guitarist Stone Gossard, one of her many friends from what she terms “the small fishing village of Seattle.” The talk of rock and roll spurred Olson to roll up the sleeve on his black T-shirt to reveal the fresh ink: a vaguely Celtic design that resembles a series of curvaceous uppercase As linked together. The tattoo represents the disulfide bonds that form a knot at the center of the chlorotoxin molecule.
Olson’s tattoo is a tribute to not only chlorotoxin but also a range of similar peptides that he’s now investigating as possible weapons against cancer and other diseases. Using a custom-written Python program that can troll through decades’ worth of genomic databases on venoms, his lab has identified hundreds of thousands of molecules that share chlorotoxin’s central knot of disulfide bonds and thus may form the basis for new cancer-fighting drugs.
To fund this research, Olson is expanding upon the crowdfunding techniques that were so vital to Tumor Paint’s growth. His website for Project Violet offers a range of rewards for different contribution levels, much like on Kickstarter. For $100, donors can “adopt a drug candidate” and then track its progress; for $25,000 they can have dinner with Olson.
But conjuring a drug to life is a more complex process than, say, recording an album. The vast majority of pharmaceutical concepts that seem brilliant on paper end up leading nowhere, even after years of toil. When the stakes are so high, crowdfunding becomes much more complicated—especially when the one raising the money is also the funder’s doctor. “When we’re talking about a bedside physician versus a bench scientist, we’re talking about physicians who have deep levels of trust with patients,” says Josh Perry, an assistant professor at Indiana University’s Kelley School of Business who specializes in the ethics of health care. As a model for other doctors, he warns, this kind of setup could be problematic. “They are basically trading on the depth of that relationship. It can be done, but I think it’s delicate.” Perry also worries that physicians may be prone to overstate an innovation’s promise—not because they’re dishonest but rather because they care so much about their patients. “Even a physician with the greatest of intentions can become very emotionally invested in the success of their research,” he says. “There’s just lots of potential for compromised judgment on all sides.”
Tumor Paint is a perfect example of an innovation that has received disproportionate attention because of a doctor’s passion. The compound still has another two phases of clinical trials to complete to prove its safety and efficacy to federal regulators. But during Olson’s stirring onstage performances, it can be easy to forget that so many hurdles remain. Even some people who believe in the promise of Tumor Paint worry that Olson’s compelling pitch obscures the long journey ahead—including Patrik Gabikian, the former resident who first brought chlorotoxin to Olson’s attention. “I’m not going to mince any words—as a person who takes care of patients with serious diseases, I don’t like to believe in a lot of hype,” says Gabikian, now a neurosurgeon at Kaiser Permanente Los Angeles Medical Center. While he understands that a certain amount of promotion is necessary to bring a new technology to market, he worries that Olson’s knack for storytelling will give “undue hope” to people suffering from cancer.
Olson quickly brushes off such criticisms. “Patient-based funding is a huge part of what drives biomedical research. Often it’s done indirectly—through foundations that offer grants,” Olson says. “We tell the families about our failures as well as success and are completely transparent about spinouts and such.”
Though accepting money from patient families may make ethicists squeamish, traditional methods of funding have their own problems—a fact well illustrated by the challenges faced by TransMolecular, the company developing chlorotoxin as a treatment for gliomas. Despite all the initial fanfare, TransMolecular couldn’t publish the results of its Phase II trials when they were finally ready. Sontheimer blames this failure on the 2008 economic crisis, which caused venture capitalists to grow leery of backing biotech companies with idiosyncratic products. TransMolecular’s CEO died unexpectedly the following year, and his successor decided that the best course of action was to liquidate. Sontheimer still holds out hope that the company that purchased TransMolecular’s assets will eventually continue his work.
If a little old-fashioned salesmanship can help Tumor Paint avoid these kinds of bureaucratic pitfalls, Olson is willing to endure whatever criticism comes his way. Perhaps the ethical purists might feel rather differently if they, like him, had to walk around a pediatric cancer ward every day.
Brain surgeons can’t easily distinguish a tumor from healthy tissue. Jim Olson’s Tumor Paint solves this problem by giving tumors an eerie and distinct fluorescent glow. —Jason Kehe
Step 1 Olson needed a compound that would locate only tumor cells. The answer: chlorotoxin, a (nontoxic to humans) molecule found in the venom of the deathstalker scorpion.
Step 2 Chemists attach a fluorescent dye—the FDA-approved indocyanine green (a)—to laboratory-made chlorotoxin (b). The resulting compound glows in near-infrared light.
Step 3 Before surgery, Tumor Paint—which can cross the blood-brain barrier—is injected into the patient’s bloodstream through an IV and begins circulating within the body.
Step 4 The outsides of tumor cells contain a protein healthy cells don’t: Annexin A2 (a). Research shows chlorotoxin (b) binds to Annexin A2 and from there seeps into tumor cells (c).
Step 5 It can take an hour or two for enough of the compound to accumulate in a tumor to be useful. Even then surgeons still can’t see their targets with the naked eye. Instead, they point a near-infrared laser at the area—often in the hard-to-operate-on brain—and a special camera captures the light emitted from the Tumor Paint. Tumors appear on a monitor as ghostly-green blobs.
|Evernote helps you remember everything and get organized effortlessly. Download Evernote.|