On the shoulders of giants
A new generation of Hutchinson Center scientists joins the battle against cancer. Together, they seek to build on the knowledge amassed by research pioneers.
The science of outsmarting rogue cancer cells looks very different for researchers starting out in the 21st century from the way it did decades ago.
Benefiting from many years of key—and sometimes unexpected—discoveries at the Hutchinson Center and other scientific institutions around the world, a new generation of investigators is now uniquely poised to advance disease prevention, detection and treatment in new directions.
 (clockwise from top left) Dr. Elahe Mostaghel Dr. Patrick Paddison Dr. Toshiyasu Taniguchi Dr. Amanda Paulovich |
Of course, challenges remain amid the advances. The same evolving technologies that have jumpstarted progress have also raised new questions and produced fresh complications—how to make sense of unprecedented mounds of data, for example.
"The scale of our experiments has changed dramatically," said Dr. Patrick Paddison, a biologist who joined the Hutchinson Center’s faculty last summer.
Paddison, and Drs. Elahe Mostaghel, Amanda Paulovich and Toshiyasu Taniguchi represent just four of the Center’s relatively early career faculty whose work in this new context is attracting attention. Their research spans a diversity of potentially lifesaving ideas, from improving therapies for aggressive prostate and ovarian cancers to unlocking genetic- and protein-based secrets about disease.
A revolutionary road
When Dr. Patrick Paddison explains to his family what he does for a living, he favors a simple analogy: Imagine you’ve just been presented with a particularly exotic car and asked to figure out how it works—no blueprints included.
 Dr. Patrick Paddison |
At a basic level, that’s what biologists like Paddison do—only in cells, of course, not cars—using a relatively new technology called RNA interference. RNAi, as it’s known for short, allows scientists to switch off particular genes, creating the potential to determine which genes may be implicated in all sorts of diseases. Their hope is to spur more effective treatments for everything from cancer to HIV to degenerative brain conditions.
RNAi technology "has sort of been a revolution," Paddison said. "It has allowed us to address questions we wouldn’t otherwise be able to address."
The idea of manipulating genes to uncover clues about human diseases isn’t new, but it wasn’t nearly as plausible in mammals before biologists essentially stumbled upon the RNAi phenomenon scarcely 10 years ago. Model organisms like yeast, fruit flies and worms have lent important insights and continue to serve important roles, but they’re fundamentally different enough from humans that limitations inevitably arise.
In some ways, RNAi technology epitomizes how dramatically the scope of biomedical research has widened just since the turn of the 21st century, leaving a new generation of cancer researchers like Paddison uniquely situated to build upon past breakthroughs.
"We’ve gone from racks of test tubes to robotically handled multichambered plates, from looking at how single genes function to probing almost all genes simultaneously," Paddison said.
The challenges, he said, are making sense of the mounds of new data that these powerful tools can generate and deciding which questions to ask.
Growing up in New Orleans, he always felt a certain curiosity about the way things work but never had a passion for science, per se. At one point, he thought that he wanted to be a psychologist. A college neurobiology class changed his tack. "I was immediately hooked," he recalled.
After graduation, he had the good fortune to land a job as a research technician working for Drs. Lee Hartwell and Steve Friend at the Hutchinson Center. The seasoned biologists were using budding yeast cells to identify genes that determine whether a cell is dividing normally, leading to key insights about cancer, which arises from abnormal, uncontrolled cell growth.
The post was a formative experience for Paddison. Hartwell and Friend "set me on the research path I find myself on today," he said.
Today, Paddison and his lab are using techniques based on RNAi to target one primary question: When we look at the some 200 types of cells in the human body, what genes allow them to maintain their particular functions, identities and survival? With the answers, he hopes to find new gene networks to target for therapies for various illnesses and to learn more about how RNAi itself may be used to treat diseases like cancer.
How to outsmart a clever cancer cell
As a new physician treating leukemia and lymphoma patients in Japan, it didn’t take long for Dr. Toshiyasu Taniguchi to spot a perplexing pattern.
At first, the anti-cancer drugs would slay unwelcome malignant cells with some success. But, inevitably, some of the cancers would come back—often with new vigor, defying the drugs that once halted them.
 Dr. Toshiyasu Taniguchi |
"We need something new to improve the treatment of patients," he said recently in his office at the Hutchinson Center, where he joined the faculty in 2004. "The drug-resistance problem is huge."
Born in Tokyo to a semiconductor-engineer father and a science-teacher mother, Taniguchi grew up with a natural fondness for science. By the time he reached high school, all that was left to settle was which route to take: physician or researcher.
At the time, he opted for practicing medicine, believing it was "more directly related to human happiness."
But spending quality time with tiny proteins and tissue samples has its own rewards. On a recent afternoon, it was impossible to overlook the sardine can-sized digital timer clipped to Taniguchi’s button-down shirt placket—a tactic to prevent misplacement during a protein-analysis procedure, but also a symbol of sorts. "The point is that I still enjoy doing some experiments myself," he explained.
The crux of Taniguchi’s research is a natural process called DNA repair, which scientists have suspected for many years plays a role in cancer development. If we think of DNA as a genetic blueprint, then mistakes in those vital instructions can lead to health problems. The body normally has ways of fixing these bloopers, but those repair methods can malfunction, sometimes resulting in a greater risk for diseases like cancer.
Taniguchi and his colleagues have found that a window into this process is a rare genetic disorder called Fanconi anemia, in which the majority of patients go on to develop cancer. When he was a postdoctoral researcher at Dana-Farber Cancer Institute in Boston, Taniguchi’s group revealed several genes associated with Fanconi anemia form a "pathway" that interacts with two of the best-known genes associated with cancer risk, BRCA1 and BRCA2. If those genes are damaged, then breast and ovarian cancer, and other diseases are more likely to occur.
Interestingly, that same DNA damage means chemotherapy drugs, which kill cancer cells by exploiting that damage, are quite effective in most cases—at least at first. But those drugs gradually lose their effectiveness, and no one has fully understood why.
Taniguchi’s lab and collaborators recently discovered a particular cell event— unlike any other ever identified in relation to cancers and drug resistance—that seems to explain why popular platinum-based chemotherapy drugs like cisplatin and carboplatin fail over time to shrink ovarian tumors.
"People didn’t think of this possibility before," Taniguchi said of the findings. "This phenomenon reflects that cancer cells are really creative in order to survive, and we need to be more creative than cancer cells."
Tailoring the future of cancer therapies
Dr. Elahe Mostaghel was one of those kids who knew back in elementary school that she wanted to be a doctor. The science of living things fascinated her.
But she never set out to specialize in prostate cancer. That choice, as she tells it, was more a series of circumstances.
 Dr. Elahe Mostaghel |
By the time she finished her first year as a Center postdoctoral fellow in 2005, working with the gravely ill had weighed on her. She was ready to explore something new. Early on, she crossed paths with two of the Center’s prostate cancer investigators, Drs. Bruce Montgomery and Peter Nelson, and found their enthusiasm infectious.
Around the same time, her interest turned more personal: Her father was diagnosed with prostate cancer.
His treatment has since gone well, and Mostaghel’s involvement in advancing new directions for prostate cancer treatments has flourished. "For my family, it has been reassuring that I have access to this field," she said during a recent interview.
Now a junior faculty member at the Center, she splits her time between seeing patients through the Seattle Cancer Care Alliance, the Center’s treatment arm, and working as part of Nelson’s laboratory on research to bolster prostate cancer treatment.
For the past 70 years, the most popular method of buying time for prostate cancer patients has centered on suppressing male hormones, such as testosterone, that are known to feed tumor growth. But it’s not a cure, as the cancer frequently develops a resistance to this treatment—known as androgen-deprivation or suppression therapy—and comes back in a deadlier form.
That’s one of the problems that Mostaghel and her colleagues investigate, and with promising results so far.
They recently found what may be the key to developing more effective treatments: prostate tumors appear to make their own hormones, fueling their own growth. The finding suggests future therapies may need to hit directly at the tumors themselves—a departure from current regimens, which target hormones circulating throughout the body.
Even so, there’s no one-size-fits-all approach for prostate cancer patients, and researchers are moving closer to tailoring treatments to an individual patient’s makeup. One of Mostaghel’s newest projects is an attempt to develop simple, less-invasive blood tests that can relay crucial information about hormone levels in tumor tissue, with the hope of better guiding oncologists’ treatment decisions.
"That’s the future," she said. "We’re going to get better about our understanding of cancer therapy and how to target it."
Mostaghel sums up her generation’s main advantage in one word: access. Gone are the days of enduring headaches and paper cuts while photocopying unwieldy stacks of scientific journals to peruse. Instead, swelling electronic repositories serve up searchable access to documents in minutes, informing her work—and even inspiring her to strike up a few collaborations with scientists she has never met in person.
Focusing on the ones that get away
It took only a few stray cancer cells to direct Dr. Amanda Paulovich’s research path.
While training in both clinical medicine and basic science, she treated oncology patients who appeared cured after treatment, but the best of scans couldn’t detect a small number of cells that sometimes escaped the original cancer site. Those renegade cells went on to become hard-to-stop metastatic cancer.
 Dr. Amanda Paulovich |
The quest for Paulovich became—and remains—to find miniscule molecules in the body in order to diagnose and eliminate cancer long before it becomes a tumor or errant cells.
This promising field of biomarker discovery is in its infancy. The challenge and potential of such work led Paulovich to the Hutchinson Center five years ago to direct a 20-member Early Detection Initiative.
Genes instruct cells, and proteins do the work that drives both cellular health and disease. Genomics is the study of gene sequences; proteomics analyzes proteins.
So while genes hint at the likelihood of developing a certain disease, proteins show what is currently happening in a patient.
The discovery that proteins are leaked by tumors into the blood and urine could lead to better diagnostic tools for cancer detection.
Thousands of potential biomarkers have been discovered, and this list continues to grow. But the sobering reality is that very few of these candidates have been validated, and even fewer have reached patients.
Paulovich’s lab is developing technologies to rapidly screen large numbers of candidate protein biomarkers in the hundreds of patient samples necessary for verification. Identifying these key biomarkers have disease implications far beyond cancer.
Paulovich and her colleagues recently took a big step forward in overcoming limiting factors validating biomarkers for clinical use: a lack of standardized technologies and methodologies.
A national scientific network that includes Paulovich’s team may have solved that dilemma by creating a new method for detecting and quantifying protein biomarkers in body fluids.
This novel approach holds the promise of ensuring that only the strongest biomarker candidates will advance down the development pipeline.
The chief aspect of their research is to reproduce uniform results across laboratories in a variety of instruments.
"We’re pushing the cutting edge of what’s possible with mass spectrometry," Paulovich said of the complex machines her team uses to measure molecules. "We’ve been one of the labs pioneering uses of mass spectrometry and proteomics to find biomarkers.
"If the technologies meet their potential, we’ll stop treating patients based on population averages. The idea behind personalized medicine is figuring out what’s the ideal intervention for you, which will cut costs and improve our treatments—that’s the ultimate goal. If we can make it work, it will have a giant impact."
There are already examples of this approach in lung and breast cancer treatments. "It’s just a matter of making what are now the exceptions, the rule," she said. "I think we’re only a decade or two away."
Paulovich is a bold and tenacious researcher, which she credits to her lengthy dual training in medicine and science. "A scientist who’s been immersed in the culture of medicine and treating patients has a far deeper understanding of what would and wouldn’t fly. I get it, on both sides," she said. "If I had just been in the lab, I wouldn’t have the advantage of understanding medicine well enough to tie everything together."
