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'Research at the Frontier'
Liotta, Zerhouni Kick Off Summer Lecture Series for Interns

By Rich McManus

Photos by Ernie Branson

On the Front Page...

As if cancer researcher Dr. Lance Liotta's talk on inventing new tools to detect cancer-host interactions at their earliest moments wasn't attraction enough, the summer students who packed Masur Auditorium June 11 for the kickoff of an eight-lecture series for interns were also treated to introductory remarks by NIH's new director Dr. Elias Zerhouni, who advised them to follow their imaginations, take advantage of the "largest concentration of top biomedical scientists in the world," and dare to "use the side roads and explore — don't use I-95."


The highway reference is hard-won; Zerhouni commutes daily to Bethesda from the greater Baltimore area. But he was serious about avoiding the main drag. "It really is a great pleasure to meet students," he began, then quipped: "At Johns Hopkins, where I was executive vice dean, they were always worried that I'd say something wrong to the students, so they didn't let me speak until it was time for graduation."

He said a defining moment in his own career as a scientist occurred in ninth grade, when an inspirational math teacher — who was used to giving his charges interesting problems — gave Zerhouni and his peers, unbeknownst to them, Fermat's Last Theorem to solve. The teacher never let on that the theory had gone unproven for 300 years, and Zerhouni was perhaps predictably stumped.

NIH director Dr. Elias Zerhouni counseled summer students to avoid the metaphorical Interstate 95 in choosing scientific paths.

"We spent about a month and a half trying to figure it out," he said. "But the experience taught me something: This is science. This is what it means to be explorers of the unknown...Don't expect your teachers to give all the answers. The problems you choose are important — pick ones worth going after."

He admitted he still doesn't understand the proof of Fermat's Last Theorem that was elaborated several years ago, but doesn't regret having been a searcher. "Don't be conventional," he urged. "Take advantage of your opportunities. We're counting on you to find out what it is we don't know."

Liotta, who is chief of NCI's Laboratory of Pathology, which employs about 20 youngsters every summer, said that DNA, as encoded in the genome, is merely an information archive, but that proteins do all the work. "The information flow is mediated by and through proteins," he said, then modified the signature quote of the 1967 film The Graduate: "The future is proteomics."

By studying how proteins signal one another and interact, scientists can discover the "wiring diagram" of cells, Liotta said. "It's a very, very hard field, but it promises direct patient benefit."

  NCI's Dr. Lance Liotta

He said a new paradigm in cancer diagnostics is emerging, which is fortunate because "cancer is usually diagnosed when it's too late — once cancer has metastasized, it's too late, even for today's advanced treatments."

Liotta and his colleagues, including Dr. Emanuel Petricoin of the Food and Drug Administration, are trying to take advantage of the comparatively lengthy premalignancy phase. "Ten, 20, 30 years can elapse before diagnosis of an overt lesion," he said. Two techniques developed in his lab offer windows into this phase: laser capture microdissection enables researchers to carve out a specific nexus of normal and premalignant tissue for detailed analysis of the molecular "microecology." And a single drop of blood can yield physical evidence of its donor's tendency toward cancer in a new system that marries the pattern-recognition power of software (from the field of artificial intelligence) with mass spectrometry.

In Liotta, the summer students heard an impassioned medical detective, carefully building the case for how such studies might help patients, ceaselessly asking of the proteins under his surmise, "Who's talking to who, who's modifying who? What signaling pathways are dominant, which are deranged?"

A central question in cancer biology asks if the big clumps of unstoppably growing cells are caused by a faster growth rate or a slower death rate; Liotta's group has found, through elevated levels of the Akt protein, that some cancers take advantage of healthy cells by suppressing the normal signal telling the cell to die. "So in the premalignant lesion, it's not an increase in growth, but a suppression of death that characterizes the cells."

Liotta foresees in the near future an array of microchips — "baited" with normal, premalignant, and cancerous protein samples — that can help doctors diagnose cancer and then tailor treatment to individual patients, determining whether their interventions are hitting the mark or not. "We will be able to attack the signaling pathway at a variety of points, with lower doses and lower toxicity."

The blood-drop analysis, or SELDI (surface-enhanced laser desorption and ionization) process, yields multiple proteomic patterns in serum, subpatterns of which can signal cancer in tissue, Liotta said. His lab has teamed with a private firm, Correlogic, whose specialty is pattern-recognition in the service of terrorist detection. The NCI lab is using the company's algorithms to seek "cellular terrorists." The single drop of blood required for the test, which blasts specimens with a laser, then measures "time of flight" of proteins, yields "tens of thousands of protein peaks for each drop...Certain key peaks seem to be associated with cancer," Liotta said.

The assay has been applied first to prostate cancer; patients who test positive for prostate-specific antigen (PSA) are enrolled to see whether SELDI can produce a characteristic "signature" of disease. So far, in a 62-patient "training set," the new technology has yielded seven key mass-charge values that appear to distinguish cancer patients from normal controls. Scientists have no idea yet which proteins are responsible for the peaks, but they have been 95 percent successful in predicting prostate cancer (later confirmed by biopsy), which can help a doctor manage a patient who presents only with a marginally elevated PSA level.

Liotta and collaborator Dr. Emanuel Petricoin of FDA run the world's first joint proteomics program, and invite visitors to see the operation.

Liotta said ovarian cancer is also being studied for telltale proteomic patterns. Normally a "silent killer" that goes undetected until it is too late, ovarian cancer could be far better managed if found early. Emerging tests have been "very specific, and very sensitive" in detecting the cancer, Liotta reported. "This looks very promising. We hope to move detection to earlier stages (I and II, for example, rather than III and IV, by which time remission rates are far harder to attain).

"This system will become smarter and more accurate as time goes on," predicted Liotta, who plans to make the diagnostic system available on the Internet. "It's a new concept in diagnostics. We foresee a new era of personalized molecular medicine."

He then invited anyone interested to spend time this summer in labs of the joint FDA-NCI Clinical Proteomics Program, which is the first of its kind in the world, said Liotta. "It's the only program that is applying proteomic technology to actual patient research."

The lecture series, sponsored by the Office of Education, has four remaining talks, all in Masur Auditorium, Bldg. 10, from noon to 1 p.m.: July 9, "Beyond Transcription: Novel Mechanisms for Regulating a Bacterial Development Switch," Dr. Susan Gottesman, NCI; July 16, "Bioinformatics and Its Role in Biological Discovery," Dr. Tyra Wolfsberg, NHGRI; July 23, "Stem Cells and the Central Nervous System," Dr. Mahendra Rao, NIA; and July 30, "Protein Structure Determination Using Electron Microscopy," Dr. Jacqueline Milne, NCI.

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