Winter 2007

Buck Rogers and the amazing death stalker scorpion

Dr. Jim Olson's invention of tumor paint that lights up cancer cells sounds like science fiction. But in reality, it could revolutionize cancer surgery and tumor detection.

By Ignacio Lobos




The death stalker scorpion, as its name implies, hides under stones and natural burrows in the dark of the desert night and waits for a victim to go by. Then it strikes, grabbing a cricket or an earthworm or some other unfortunate critter with its claws. If the victim squirms too much or puts up a fight, the death stalker stings it with a quick stroke of its tail, delivering a toxic cocktail and swift death.

Dr. Jim Olson credits teamwork for the discovery of tumor paint.
The death stalker scorpion (Leiurus quinquestriatus) is an aggressive and jumpy desert dweller its habitat ranges from the Middle East to North Africa but not a particularly remarkable member of its species. It grows to about five inches in length and its color varies according to where it lives.

What is extraordinary about the death stalker is the poison that it delivers when its venom glands are electrically stimulated in the heat of the fight. Because it kills 50 percent of its victims in a controlled environment, the death stalker is considered one of the deadliest scorpions in the world.

Its sting is dangerous to humans as well, particularly children. The poison travels quickly through the body, causing fever and convulsions. Heart rate and blood pressure spike, and the lungs fill with fluid. Complications may lead to heart or respiratory failure and death.

It's a complex venom that the death stalker delivers, filled with enzymes, enzyme inhibitors, histamine and several neurotoxins that destroy nerves or nervous tissue. One of the key ingredients in this toxic brew is chlorotoxin. And it's only a matter of time before it becomes not a killer but an invaluable tool in the fight against cancer.

A Buck Rogers kind of moment

Chlorotoxin was not in Dr. Jim Olson's mind 20 years ago when he was wrapped up in his university studies. But he was consumed by a nagging question: "Wouldn't it be interesting if we could light up a cancer cell?"

It was an important question shared by others, and many scientists have tried to answer it. For surgeons who specialize in brain cancer, it is a key issue. Brain cancer is extremely difficult to treat, and often delicate, imprecise surgery is the only recourse.

A surgeon has to determine where cancer starts and ends before a single cut is made, but under the naked eye, normal brain cells look identical to tumor cells. Cut too much, the patient may suffer irrevocable damage. Cut too little and the cancer is likely to return. If only there was a way to tell them apart, a way for cancer cells to stand out in their full malignant glory so a surgeon could pluck them out with a precise scalpel cut, leaving healthy tissue untouched. With 80 percent of malignant cancers recurring along the edges of the surgical cut, there's a lot of room for improvement.

The idea was solid but the technology wasn't there, Olson recalls. Even his adviser told him to focus on something a bit more grounded. "That's a pretty nice idea, Buck Rogers, but what are you going to do about it," he remembers being told.

Olson is an affable guy, quick to smile and with a good sense of humor (one of the books he's written is titled "Clinical Pharmacology Made Ridiculously Simple," and its cover shows a pair of fear-stricken cells under attack by pharmacological missiles). Although he has been singled out as one of the most innovative researchers working at the Hutchinson Center, he remains modest and approachable. His focus is on his patients.

That's why after completing his studies, he didn't have time to think about lighting up brain cancer cells. He was busy treating cancer patients, publishing papers and doing other research &mdsh; always aware of one painful fact: brain cancer's death toll.

The most common brain tumors are known as gliomas. This year, more than 20,000 children and adults will be diagnosed with malignant tumors of the brain or spinal cord. Nearly 13,000 will die. Gliomas are nasty killers. Patients often suffer headaches, nausea, seizures and cranial nerve disorders. The average survival time is 12 months. Few patients survive past three years.

A culture of ideas breeds knowledge

Olson was barely four years old when he pulled an encyclopedia from the bookshelf. It was a Reader's Digest family medical book, and its images fascinated him. "I told my parents I wanted to be a doctor. And after that, I didn't waiver very much at all. I stuck with it," he said.

In time, the medical books got more complicated and infinitely more fascinating. Medical research became an important facet of his life, but he also found himself gravitating toward cancer patients and their families. He was moved by his younger patients' tenacious fight against the disease and by the volunteers who participated in clinical trials. In recent years, after becoming a dad to two girls, Olson became even more sensitive to the trauma of his young patients.

"The volunteers, some of them who were going to die of cancer, had nothing to gain by coming in for brain scans. To me, it was so generous that they would use their precious time to help someone in the future," Olson said.

The volunteers underscored the importance of research for Olson. And research, he said, lights up ideas. "We write everything down," Olson said. "What we know, we owe to the culture of scientists publishing everything they learn."

And new research and discoveries were beginning to show that Olson's Buck Rogers moment was not so farfetched after all. But to get there, to light up that cancer cell, would take a massive convergence of technologies involving chemistry, biology, physics and radiology, and the combined work of neurosurgeons, engineers and biologists and a little bit of nudging from a colleague.

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And the mouse lit up

A few years back, Olson found himself talking to Dr. Richard Ellenbogen, division chief of neurosurgery at Children's Hospital and Regional Medical Center in Seattle. After discussing a particularly difficult case, in which part of a brain tumor was left behind in a young girl because the surgeons thought it was normal brain, Ellenbogen told Olson, "You guys need to come up with some way to make these cancer cells light up so that we can see them. For 20 years, I've been thinking about how to do this, and I believe your lab can come up with the answer."

Olson smiled. Ellenbogen's challenge had rekindled his own personal interest in the issue, and immediately the two began making plans to move on the project.

Researchers, by their very nature, love to do their own research. But Olson knew better. When Dr. Patrick Gabikian came on board, he was ready to start doing experiments to find a molecular target that distinguished cancer cells from normal cells, a time-consuming process with no guarantee of success. Instead, Olson told Gabikian to read. Somewhere in the scientific literature of the past several years, Olson was certain, someone had tested a substance that could help his team's search.

Six weeks later, Gabikian found a promising study on chlorotoxin the death stalker scorpion venom and cancer cells. A researcher had been trying to understand how the toxin affected the flow of salts and water through cancer cells.

Researchers also had found that chlorotoxin on its own had a unique ability to bind to glioma cells and some saw it as a possible therapeutic drug. Olson wasn't thinking drugs. He was looking for a way to light up the chlorotoxin, which would then bind to the cancer cells, making them visible.

His research group settled on a substance named Cy5.5, created by Invitrogen (now part of General Electric) for diagnostic purposes under its molecular imaging program. The fluorescent molecular beacon is visible with special equipment and Olson's team found that it coupled to chlorotoxin rather well.

Getting scorpion venom in large quantities and isolating the chlorotoxin peptide (a small protein) is difficult and expensive. So Olson's team switched to chlorotoxin developed in a lab that works as well as the native one. Even that's not cheap they managed to procure $7 million's worth for about $100,000 to conduct their experiments. The final result became Chlorotoxin:Cy5.5.

Six months later, after extensive tests, Gabikian injected one-fiftieth of a teaspoon of Chorotoxin:Cy5.5 into the bloodstream of a test mouse with human glioma.

The brains look nearly the same without tumor paint. But the diseased brain, right, lights up after Chlorotxin:Cy5.5 is applied.
"As soon as we saw the first image, that was the moment I knew it would work," Olson said about the molecular beacon, which was tried first on a tumor under a mouse's skin. In another test, a mouse's intensely lit brain tumor exceeded expectations a tumor as small as 1 millimeter in diameter, about the size of a dot on this page, lit up without lighting up surrounding normal brain tissue.

Drs. Mandana Veiseh and Barham Bahrami then tried a mouse with prostate cancer. It also lit up. Other cancers also lit up and soon after, Chlorotoxin:Cy5.5 had earned a nickname: tumor paint.

Current technologies, including magnetic-resonance imaging (MRI), distinguish tumors from healthy tissue only if more than 1 million cancer cells are present. Tumor paint sees cancer cells much better than an MRI as few as 200 cancer cells.

Paint me a picture

Brain surgeons rely on their senses to excise glioma tumors from patients. They look at color, texture and blood supply to find the tumor, but despite their skills, it's an incomplete picture. Tumor paint, and the imaging equipment to see it as they operate, is likely to make surgeries more accurate and safer, Olson believes.

Olson is hopeful that tumor paint will be in surgical rooms in less than two years. But first, they have to complete a battery of tests and toxicity studies before seeking approval from the U.S. Food and Drug Administration to begin clinical trials. So far, the signs are positive. Despite its source, chlorotoxin on its own does not appear to cause toxicity in mice or humans, as shown by several studies. It does cause paralysis in crayfish and is likely toxic to some other living organisms.

In the meantime, Olson keeps slipping into those Buck Rogers moments, stepping into a future filled with promises of better cancer treatment.

"We were told that lighting a cancer cell was too speculative, that it couldn't be funded," he said. "We had to seek private funding to make it happen. It couldn't have been done without private donations."

This is "a huge step," and may open the door to other cancer-fighting strategies, said Olson, whose team is collaborating with Dr. Migin Zhang's team at the University of Washington to develop nanoparticles coated with chlorotoxin to directly deliver therapeutic drugs to fight the cancer cells at the cellular level, sparing a person the painful effects of chemotherapy and radiation, which affect the whole body.

Olson said Chlorotoxin:Cy5.5 also has the potential as a noninvasive screening tool to help detect lung, skin, cervical and esophageal cancers. And likely will help detect breast, prostate and testicular cancers at an early stage.

"In academic science, everybody shares their work. True, it's competitive but we build upon each other's discoveries," Olson said. "That's why I love this kind of research."

Private donations and teamwork lead to tumor painting

The development of Dr. Jim Olson's tumor paint was made possible thanks to a partnership between the Hutchinson Center, Children's Hospital and Regional Medical Center and the University of Washington.

Olson's lab is also partnering with TransMolecular, Inc., a Cambridge, Mass.-based biotechnology company, to advance tumor paint to human clinical trials.

But it was private donations from parents of cancer patients and other Center supporters who funded a large portion of Olson's pioneering work. The Children's Hospital Brain Tumor Research Endowment and the Jordyn Dukelow Memorial Guild also made large contributions.

"Parents of our pediatric brain tumor patients decided on their own that federal institutions were not funding innovative research early enough, fast enough or well enough," Olson said. "These motivated parents have been actively raising money so that our lab can act immediately on good ideas. Without the private funding from patient families, we might not have tumor paint."

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