Research Notes

Monkey Knockout In an early step toward developing a potentially invaluable animal model, scientists, for the first time, have genetically modified a nonhuman primate (A.W. Chan et al., "Transgenic monkeys produced by retroviral gene transfer into mature oocytes," Science, 291:309-12, Jan. 12, 2001). Researchers at the Oregon Regional Primate Research Center at the Oregon Health Sciences University in Portland used a replication-incompetent retrovirus as a vector to deliver the gene for green fluorescent protein (GFP) into a rhesus monkey oocyte (a mature egg). According to lead author Anthony W.S. Chan, the procedure, in the works for two and a half years, is a tricky one. Oocytes are hard to come by, and relatively little is known about primate embryology. Of the 224 eggs fertilized, half of them developed; forty embryos were selected and placed into 20 surrogate monkey moms. Of the five successful pregnancies, there were three live births. But tests have shown that only one monkey, called ANDi (stands for "inserted DNA" spelled backwards), is carrying the inserted gene. Chan, a staff scientist at the primate center, is quick to add, however, that because ANDi is so young, researchers have been able to take only limited tissue samples. As a result, they do not yet know the full extent of GFP expression. "We don't know much about how an exogenous gene in a monkey will be regulated," says Chan, adding that understanding GFP regulation in ANDi will be an important step toward determining if a better monkey model will help bridge the considerable leap between testing therapeutics on mice and testing them on humans. The ultimate goal: "knockout monkeys" that, like knockout mice, have had endogenous genes replaced with genes of interest, possibly disease genes. Chan says that he and his colleagues plan to consult with biomedical researchers to determine which genes--for example, those that contribute to Alzheimer's disease--might make good candidates for future gene transfer studies. --Eugene Russo Targeting Telomerase to Prevent Cancer The ribonucleoprotein telomerase plays an early role in cancer by tacking 6-base DNA pieces onto chromosome tips, which immortalizes them. In culture, agents that block telomerase can send cancer cells into apo-ptosis, but this is a final death dance. Now, researchers from the University of Texas Southwestern Medical Center in Dallas have glimpsed peeks at earlier telomerase action. The results suggest a new way to screen potential anti-cancer agents, and perhaps even to intervene early in carcinogenesis. Demonstrating the ability of anti-telomerase agents to block immortalization is challenging, because spontaneous immortalization is an extremely rare event. To enrich for this possibility, postdoctoral researcher Brittney-Shea Herbert and department of cell biology professors Woodring Wright and Jerry Shay cultured noncancerous epithelial cells from a 31-year-old woman who has Li-Fraumeni syndrome, a familial cancer syndrome caused by a mutation in the tumor suppressor gene p53 that often manifests as early-onset breast cancer (B.-S. Herbert et al., "Effects of chemopreventive and anti-telomerase agents on the spontaneous immortalization of breast epithelial cells." The Journal of the National Cancer Institute, 93:39-45, January 2001). These cells become cancerous when the second copy of p53 mutates, along with a second tumor suppressor gene called p16. The researchers treated cells with four known chemopreventive agents (oltipraz, difluoromethylornithine, tamoxifen, and retinoic acid), as well as two telomerase inhibitors (an antisense oligonucleotide to the template region of telomerase RNA, and a vector-introduced dominant mutation that disables the catalytic subunit of telomerase), plus controls. Retinoic acid, tamoxifen, and the two telomerase inhibitors each significantly squelched immortalization. "This is the first paper to show that inhibiting telomerase in preimmortal human breast epithelial cells can prevent immortalization. We also showed that some established chemopreventive agents can prevent immortalization, a critical if not rate limiting step in cancer progression," says Shay. This is important news for women at very high risk for breast cancer, such as those who have BRCA1 mutations or have already had the disease. In a broader context, the demonstration that non-toxic levels of telomerase blockers and known chemotherapeutics act this early might be useful in preventing cancer. "Many millions of people are at increased risk for the development of cancer, such as smokers, former smokers, people who work in the chemical industry, and those who have minimal residual disease. We have very little to offer them to reduce the possibility of primary cancer or relapsing," Shay adds. The NCI and the Susan G. Komen Breast Cancer Foundation supported the project. --Ricki Lewis

Research Notes

Monkey Knockout

Interested in reading more?

Become a Member of