Editor’s note: Science Scan is a roundup of recently published biotechnology-relevant research.
In a weird set-to between Catch-22 and Russian roulette, the brain cells of Huntington’s disease (HD) patients measure the onset and progress of their affliction by the proliferation of CAG repeats. CAG stands for the uncontrolled reiteration of triplet codons cytosine-adenine-guanine which express the amino acid glutamine in mutant huntingtin genes. Normal, healthy individuals encode CAGs in their brain cells up to 39 repeats, with no ill effects. But 40 iterations begin to spell the onset of HD. The higher the number of mindless expansions, the earlier in life the disease flares up. Forty-eight repeats spell symptoms at age 26; 50 at 25 years of age; 60 at 14; 70 at 11 years old.
Now there are novel molecular manifestations of Huntington’s disease the aggregation of mutant huntintin proteins encoded by the HD gene. “Expression of expanded CAG repeats forms these aggregates,” observed cell biologist Crislyn D’Souza-Schorey at the University of Notre Dame. She is senior author of a paper in the March issue of Nature Cell Biology titled: “Arfaptin 2 regulates the aggregation of mutant huntingtin [htt] protein.”
“We’ve identified a protein that localizes to and we think plays an active role in the formation of these huntingtin aggregates,” D’Souza-Schorey told BioWorld Today. “They morphologically resemble mutant huntintin aggregates characteristic of HD. The role of aggregates in cells is not quite clear,” she pointed out. “The fact that we saw a higher number of aggregates as disease progressed indicated that it correlated with toxicity. On the other hand, there was another part suggesting that aggregation was a protective mechanism, rather than pathogenic.
“Arfaptin2,” she continued, “is a protein we discovered. Mutants of arfaptin2, when crossed in the cell with mutant htt that’s present in these aggregates, blocks the ability of mutant htt to form the aggregate. We made antibodies against arfaptin2, and localized it in HD mouse models transgenic for mutant htt. And this molecule appeared to be upregulated. That’s essentially what we reported. So if the aggregates were indeed pathogenic toxic the fact that these mutant proteins disrupt them is a potential target for therapeutic intervention.” D’Souza-Schorey expressed her “interest in actually making transgenic mice with either the wild-type arfaptin2 or the mutant arfaptin2, and eventually crossing them with HD mice to see what the end result might be.”
Aspirin Tapped For New Gig As Antiviral By Clamping Down On Prostaglandins
Little old aspirin may put on another hat as an antiviral therapeutic. Its first target is likely to be human cytomegalovirus (HCMV) a member of the herpesvirus family that causes cold sores, genital infections and sometimes shingles. HCMV rarely causes problems in healthy adults. However, its infection during pregnancy is the leading cause of birth defects, accounting for thousands of hearing-impaired children born every year in the U.S. HCMV infection of an embryo in utero may result in malformation and fetal death. In people with compromised immune systems such as AIDS victims HCMV can be deadly.
Drugs like aspirin, called cyclooxygenase-2 (COX-2) inhibitors, block production of prostaglandins, which bring on pain, fever and inflammation. Researchers at Princeton University treated HCMV-infected human skin cells with COX-2 inhibitors and found that the aspirin-like enzymes dramatically increased and concomitantly reduced viral production. They report this finding in the Proceedings of the National Academy of Sciences (PNAS), released electronically on Feb. 26, 2002. Their paper bears the title: ”Inhibition of cyclooxygenase-2 blocks human cytomegalovirus replication.”
To confirm that the COX-2 inhibitors were having this antiviral effect by inhibiting prostaglandin (PG) production, the authors added back a specific type of PG to the drug-blocked cells. That jolt of PG restored viral production, offering a first glimpse of its antiviral mechanism.
COX-2 is the critical site of action for anti-inflammatory drugs like aspirin, indomethacin and other non-steroidal anti-inflammatory compounds (NSAIDS), and for a growing list of specific commercial COX-2 inhibitors, notably Celebrex and Vioxx. NSAIDS have been shown to inhibit replication of other RNA and DNA viruses, which leads to the possible targeting of this pathway as an auxilliary means of controlling viral infection.
Joining Dolly et al., First Cloned Kitty Reported Doing Well, 66 Days After Delivery From Surrogate Mother
Just for the record, Nature reported in its issue dated Feb. 21, 2002, a one-page “brief communication” titled “A cat cloned by nuclear transplantation.” Its authors are in the College of Veterinary Medicine at Texas A&M University in College Station. They named their kitten “C.c.,” standing variously for “cloned cat” and “carbon copy.” Her human progenitors transplanted DNA from a female three-colored cat (Felis domesticus) into an egg cell with its nucleus removed, then transferred this embryo into a surrogate mother. C.c. was delivered by Caesarean section on Dec. 22, 2001, 66 days after embryo transfer.
Of 87 cloned embryos implanted into eight synchronized recipient queens for further development, C.c. alone survived. This the authors point out is comparable to the success rate in sheep (Dolly), mice, cows, goats and pigs. They observe that “If these odds can be shortened and C.c. remains in good health, pet cloning may one day be feasible.” However, they pointed out, “this cloning technology may not be readily extendable to other mammalian species if our understanding of their reproductive processes is limited or if there are species-specific obstacles.”
In a page-one article, The New York Times noted, “The effort was supported by a company, Genetics Savings and Clone, of College Station, Texas, and Sausalito, Calif., which wants to offer cloning to dog and cat owners. It is investing $3.7 million in the project.”