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The zebrafish is genetically very closely related to humans and can be used to establish versatile models of human disease.

Methylation patterns of specific genes also differed during development of the gut and of specialized cells such as T lymphocytes, white blood cells essential to immune defenses.

“The zebrafish is an incredibly powerful model system,” says Trede. “The fish are genetically very closely related to humans, and can therefore be used to establish versatile models of human disease. Given their rapid development and small size, they are ideally suited for drug screens to identify compounds that may be used to treat human patients.”

The three HCI labs are attempting to establish the normal methylation patterns of about 13,000 genes in the zebrafish genome during development of both embryos and specialized cells. With that knowledge, the scientists can begin to tease out the incorrect methylation patterns that contribute to leukemia, colon cancer, and developmental defects.

“When the DNA sequence of a gene is mutated, there’s no way to fix it,” says Jones. “You can circumvent the gene, but you can’t repair it. But in cancers associated with improper methylation, if we can develop a drug that

corrects the methylation pattern, the gene would behave normally again.”

HCI has already run a clinical trial of one drug that targets DNA methylation, but it affects both normal and abnormal methylation patterns. “We’re studying the details of the methylation process and refining our knowledge so we can narrow the target for future generations of cancer drugs,” says Jones.

Working together, these scientists hope to discover how methylation is established and how it goes wrong in cancer. The end goal: they want to learn how to interfere with or reverse incorrect methylation to create effective new drugs, positioning HCI to be one of the leading centers for a new type of cancer treatment.

Microarray technology involves placing tens of thousands of genes in separate locations on a glass slide and using a laser to examine them.

Closely related to humans genetically, zebrafish are small–adults are about one inch long–and they grow from egg to adult quickly. These factors make the fish a powerful model in which to identify drug compounds that may help human patients.

2006 Annual Report 13
