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Vol. LXII, No. 7
April 2, 2010

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Tsien and Capecchi
Two Nobel Laureates Fill Masur on Successive Days

Rosling, a scholar-in-residence as part of the Fogarty International Center’s 40th anniversary, is fascinated by statistics. Dr. Roger Tsien
Nobel laureates Dr. Mario Capecchi (l) and Dr. Roger Tsien visited NIH a day apart.
Nothing brings the NIH fire marshal to the doors of Masur Auditorium more readily than the appearance of a recent Nobel laureate. Two laureates gave lectures on successive days last month—Dr. Roger Tsien (2008) on Mar. 10 and Dr. Mario Capecchi (2007) on Mar. 11—and in each instance, the hall was packed. Last-minute arrivals were turned away by the dozens as safety officials kept aisles clear.

Tsien (pronounced “Chen”) gave the fourth annual NEI Sayer Vision Research Lecture, and while his talk had nothing to do with the eye, it was primarily about vision. Tsien won “the prize” for his work on GFP—green fluorescent protein—which is widely used to analyze the activity of tagged proteins within cells. One part of his talk described new work on SOGs—singlet oxygen generators—“which may do for electron microscopy what GFP did for fluorescence microscopy,” he said. The technique allows scientists to visualize molecular locations at high resolution, including synaptic junctions in neurons and the contents of mitochondria.

Turning from basic science to clinical work, Tsien described how his team has developed ingenious ways of chemically lighting up tumors so that surgeons may be able to remove them more thoroughly, via engineered molecules called ACPPs (activatable cell-penetrating peptides) that can deliver a payload of imaging agent or chemotherapy to cancer cells.

ACPPs target proteases to find and illuminate tumors, making them operable much earlier in their development. By using molecular fluorescence imaging guidance, surgeons may be able to find and eliminate tumors in much the same way that a cook scrapes the mold off a piece of cheese, Tsien reported.

A complementary tagging technique can also delineate nerve fibers, which surgeons are anxious to preserve since the fibers “can take forever, if ever, to regrow.” Again, Tsien had a colorful metaphor: “When you’re the gas company, it helps to know where the electric cables are buried under the sidewalk, if you’re going to start digging.”

By targeting the protease thrombin with an ACPP, researchers can also find arterial plaques, which can be useful in combating atherosclerosis, Tsien added.

During questions, he ruefully noted that, in meetings with venture capitalists, there was initially little enthusiasm for imaging tumors and then being able to cut them out, which might cure some cancers a bit too abruptly. Tsien admitted that when he is feeling cynical, it seems many companies are more interested in managing cancer with expensive drugs for which they can charge a lot over a long treatment period.

Capecchi (pronounced “Ca-pecky”), warmly introduced by NIH director Dr. Francis Collins—who recounted stirring details of the laureate’s early biography, including having been “essentially homeless at age 4½” and later reuniting with his mother on his 9th birthday—lingered not a moment on his personal narrative. Rather, he jumped straight to “two stories: modeling cancer and modeling neuropsychiatric disease.”

Capecchi’s team chose to model sarcoma, which is not as common as carcinoma, but “affects an important population—young adults. It is also extremely aggressive,” he said. “Eighty percent of patients [diagnosed with sarcoma] are likely to die within 5 years of diagnosis. [The cancer] has often already metastasized by the time it is recognized.”

Capecchi’s work focuses on several factors including the inducing event, the time of induction and “most importantly, the molecular environment of cancer.”

Using a mouse model of synovial, or joint, sarcoma, his team discovered that chromosomal translocation between chromosome 18 and the X chromosome is the culprit in this type of cancer. Six genes on the X chromosome are involved, as well as SYT on chromosome 18, the combination of which is cytotoxic, he said. “Muscle cell lineage is the origin of the tumor.”

His second story, involving neuropathy, began by accident, Capecchi said, during studies of Hox genes in mouse mutants. His group noticed that mice with one mutation, Hoxb8, exhibited grooming behavior at twice the frequency of their littermates.

Grooming, Capecchi said, is a behavior exhibited by all species, even C. elegans and Drosophila. “All mammals groom from the top down, from head to foot, like a person taking a shower,” he explained. Through patient observation of the hyper-grooming breed (most of which occurred at night, as mice are nocturnal), his team detected grooming behavior “at the pathological level, to the point of generating lacerations at the overgroomed sites.” Studies using knockout mice suggest that an immunological defect may lay behind obsessive-compulsive disorder and OCD-spectrum ailments in humans, and perhaps even autism and Alzheimer’s disease, Capecchi said.

Both laureates’ talks are available, without having to wait in line or mind a fire marshal’s instructions, at NIHRecord Icon

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