'Mission possible' for proteomics pioneer

Dr. Samir (Sam) Hanash's favorite example of the ever-changing nature of science is the story of his attempt 15 years ago to publish a paper in the prestigious New England Journal of Medicine.

Hanash, then a professor of medicine at the University of Michigan, had completed a study of 600 proteins in blood cells from patients with leukemia. His results showed that the relative amounts of some of the proteins differed depending on each individual's particular type and stage of disease. Hanash believed that this intriguing finding might someday help doctors customize cancer treatment instead of relying on a one-size-fits-all approach to medicine.

The journal editors weren't quite as enthusiastic, he remembers. "The scientific reviews were favorable, but the journal editors said that their readers couldn't relate to a study of 600 proteins," said Hanash, who joined the faculty of the Public Health Sciences Division in August. "That was the mindset at the time, when people were mostly studying single proteins. Today, people would ask, 'why are you studying so few?'"

Hanash's recruitment to the center is testimony to how quickly the young field of large-scale analysis of proteins — the body's workhorse molecules — is growing. His lab has earned an international reputation for its pioneering work in this research area, known as proteomics, including efforts to develop methods for sifting through tens of thousands of different proteins in the blood. The goal of this technically challenging endeavor is to identify trace proteins called markers that are leaked by tumors into the blood, which scientists believe could be used for early and more accurate diagnosis of cancer and other diseases.

In his own lab, Hanash hopes this work will yield simple tests that would allow for early diagnosis of lung, liver, pancreatic and many other cancers — diseases that can prove fatal when there is no way to detect them at early, more treatable, stages.

Among the many strengths that position Hanash well for this challenge is his collaborative approach to tackling large-scale research problems, said Dr. John Potter, PHS division director. Potter's division was able to recruit Hanash to the center thanks to gifts from the Listwin Family Foundation, the Paul G. Allen Family Foundation and the W.M. Keck Foundation.

"Sam brings an enormous wealth of experience in proteomics and in molecular diagnostics," he said. "He also has an extensive network of collaborators across the United States and the rest of the world — and already here at the center, where several grants have been submitted since his arrival. We are looking forward to an exciting time."

One of Hanash's notable leadership roles in his field was to serve as first president of the Human Proteome Organization. Somewhat like the Human Genome Project, this international collaboration seeks to catalog entire sets of proteins produced by different tissues from healthy people and those with certain diseases.

Collaboration will be critical to the search for rare marker proteins among a vast sea of others in blood serum. It has turned out that the endeavor is not the type of project that can be approached by pulling a technique out of a manual, Hanash said.

"We're starting with a situation that looks like mission impossible," he said. "It's truly like looking for a needle in a haystack."

The reason, he explained, is that blood serum is an extraordinarily complex mixture of thousands of proteins. What's more, any two proteins may exist in concentrations that differ more than a billion-fold from one another. "And the ones that are likely to be useful for diagnosing cancer are probably the ones that exist at the lower end of the range, which makes them very hard to find with standard methods," Hanash said.

To guide their search, Hanash's lab uses instruments called mass spectrometers, which can sort mixes of proteins based on their size, weight and electric charge. Since every protein is different, each has the equivalent of a molecular "barcode" to distinguish itself. The goal, Hanash said, is to find proteins that are only present in blood from people with cancer or are at detectably higher levels in people with cancer compared to healthy individuals. Hanash is also pursuing a second approach to finding cancer-specific markers, which is based on the immune system's ability to act as a "biosensor" of disease.

"It's well-known that the immune system can recognize cancer cells as abnormal and react against proteins made by tumors," he said. "One of the approaches we are using to find proteins made by cancer cells is to see what antibodies or immune cells are produced by the immune systems of people with cancer but that are not made by healthy immune systems."

Despite the great challenges they face, Hanash and other experts in the field have concluded that protein-based diagnostic tests hold greater promise than those exclusively based on genes, which are the DNA blueprints that cells use to make proteins. Since many genes are turned on or off incorrectly in cancer cells, some researchers are testing whether large-scale analysis of gene activity could be used to diagnose and classify cancers.

Hanash said that although the best recipe for success will likely involve a combination of the two approaches, proteins afford the possibility of much more sensitive early cancer-detection tests. That's because depending on how DNA information is cut and spliced together, a single gene can provide the blueprint for sometimes dozens of related proteins, each with a distinct barcode. It may be that for a given disease, only one of these related proteins serves as a good marker — a marker that would go undetected if scientists focused exclusively on its corresponding gene.

A physician's passion

Some of Hanash's passion for this project stems from his long career as a physician specializing in childhood cancers. Although he gave up practicing medicine in 2003 to devote more time to his research, his experience at the patient bedside both motivated and stimulated his research goals.

"It makes you value how little we know and how things are bound to change," he said. "It helps put the bench work into perspective."

Hanash received his medical degree from American University in Beirut, Lebanon, and a doctorate in human genetics from the University of Michigan, where he joined the faculty of the medical school in 1984.

The view of the clouds rolling in above Lake Union from his office in the PHS building is far from the only advantage of his new work environment, he said. Part of his decision to move to Seattle was the desire to work at an institution with exceptional faculty and staff whose mission is to eliminate cancer and other life-threatening diseases.

"I've been so impressed with the depth and breadth of expertise here," he said. "There are so many jewels." As he sets up his new lab, one of his first projects is to begin building collaborative relationships with many of his new colleagues who, like him, are committed to tackling the challenges of proteomics.

"Like with other tough problems, the more you chisel at it, the more progress you make," he said. "In the end, nothing is impossible."