As other biologists uncover the complexities of peroxisomes, Valle and several former students are trying to repair those that malfunction. Sabine Weller, a pediatrician and postdoc in Jutta Gärtner's lab at the University of Gottingen, Germany, has created a mouse model of Zellweger syndrome to test therapies. Weller replaced a normal peroxisomal gene called PEX1 with a mutant version known to cause one in three cases of Zellweger syndrome. A single amino acid substitution in the mutant allele, called Pex1-G843D, causes the protein to misfold, reducing its activity to less than 20 percent of its normal capacity. This so-called knock-in mouse could be used to test drugs that might stabilize Pex1, Weller says.

Nancy Braverman, a Johns Hopkins medical geneticist, succeeded in stabilizing the Pex1G843D protein in cultured cells from Zellweger patients by cooling the cells slightly. Now she's screening thousands of potential drug compounds to find one that does the same thing. Such a compound could be tested in the knock-in mice, and possibly one day in people.

“I think there's a lot of work to be done, and treatment of genetic disease is always difficult, but this is an area where we might see some real success,” Valle says.

One peroxisomal disease has already seen some limited success: ALD. Although Hugo Moser died in early 2007, Ann Moser has continued pushing for a universal newborn screening test to spot at-risk boys. Since Lorenzo's oil can prevent the disease from progressing, early detection is key. Moser and a Hopkins colleague developed a rapid blood test to detect elevated levels of very-long-chain fatty acids, a hallmark of ALD. In a small study, it appeared to be both accurate and sensitive. Now, with a Maryland state screening lab, she plans to expand the study, assessing the test on blood obtained from routine heel sticks of 5,000 Maryland newborns to make sure the screen doesn't falsely label healthy infants as sick. Moser hopes to one day put the test in place nationally. “We believe it will save families from a genetic odyssey,” she says.

		Plants are the only well-documented example of an organism that remodels its peroxisomes, and HHMI professor Bonnie Bartel of Rice University has begun probing how they do it. In oilseed plants, unlike yeast and mammals, cells revamp their peroxisomes to perform new functions as the organism matures. In seeds and seedlings, peroxisomes contain enzymes that break down stored fats and produce sugar to fuel plant growth. In mature plants, those peroxisomal enzymes are eliminated and replaced with others that improve the efficiency of photosynthesis. Bartel's team identified a pair of proteins that may help plant peroxisomes undergo this transformation. They found that mutations in two proteins, Pex4 and Pex22, cause peroxisomes in plant seedlings to retain an enzyme that's usually eliminated as the plants mature. That finding suggests that the two proteins help remodel peroxisomes during plant development, the researchers reported in 2005 in The Plant Cell. Last summer at an Arabidopsis conference in Beijing, China, they reported a second enzyme that's retained in plants with Pex4 and Pex22 mutations. Both enzymes are also retained when cells have defective proteasomes, which digest damaged proteins. Bartel suspects that, in healthy cells, Pex4 and Pex22 help mark obsolete peroxisomal proteins for removal and ship them out of peroxisomes to be destroyed by proteasomes. That, in turn, helps peroxisomes remodel as plants mature from seedlings. “As we get deeper into this, plants continue to surprise us,” Bartel says. —D.F.

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