The surprising news that peroxisomes are generated in the endoplasmic reticulum came from studies in yeast. Here, in Yarrow lipolytica, peroxisomes are green, and the actin proteins that help usher them around the cell are red.

Desperate to save their son, Lorenzo's parents, Augusto and Michaela Odone, worked tirelessly to develop a dietary supplement that suppressed the body's overproduction of a dangerous fat that destroyed the myelin sheath insulating the neurons. In the 1992 movie Lorenzo's Oil, Hollywood portrayed that supplement—the boy's namesake oil—as a miracle cure. The reality is more complicated.

Hugo Moser of Johns Hopkins University, the researcher portrayed pseudonymously in the movie as the impersonal Professor Nikolais, and Ann Moser, his wife and research partner, had studied ALD since the 1970s. After the Odones developed Lorenzo's oil, the Mosers conducted a decade-long prospective clinical trial to test its efficacy. By 2004, they'd found that the oil can prevent the disease from progressing, but it can't reverse the damage already done. Perhaps, the Mosers reasoned, an early screening test could spot ALD kids soon enough to enable the oil to hold the disease's devastation at bay. They began a determined pursuit of such a test.

The protein that's mutated in ALD patients is housed in an unappreciated organelle in the cell called the peroxisome. Defined only in the late 1960s, peroxisomes are small and spherical and distributed throughout the cell's watery interior, or cytoplasm. Most peroxisomes, which are found in fungi, plants, and animals, including humans, enclose enzymes that carry out several reactions, including breaking down certain lipids and making others, such as the plasmalogens that maintain the myelin sheath.

As the Odones' story unfolded in the late 1980s, much about the peroxisome was a mystery. But now, thanks to a small contingent of researchers, the organelle has begun to give up its secrets. Recent advances in peroxisome biology have generated hope for treating diseases, such as ALD, that involve a single crippled peroxisome enzyme. Some researchers are even developing treatments for more devastating diseases in which the peroxisome never forms correctly, such as Zellweger syndrome, which is uniformly fatal during infancy, and infantile Refsum disease with its progressive nerve damage.

Peroxisome research has also served up insights about the fundamental workings of eukaryotic cells, which make up the tissues of all higher organisms. Eukaryotic cells are organized into organelles and other compartments specialized to carry out different functions. By studying peroxisomes, scientists are getting the first exciting glimpses of how proteins are shipped across biological membranes, how organelles are formed and maintained, and how they are retooled during development. But that's just the beginning, says HHMI investigator Randy Schekman of the University of California, Berkeley, who adds that peroxisome biology is a field “about to break wide open.”

Peroxisome research received a much-needed boost in 1989 when Wolf Kunau of Ruhr University in Germany developed a way to isolate peroxisome-deficient mutants in yeast—and reveal the genes relevant to peroxisome activity. Yeast need peroxisomes to digest lipids but not to digest sugar. Kunau's team took advantage of this characteristic, screening for mutant strains that could grow on sugar but not on a lipid component called oleic acid. Kunau and other researchers then looked for genes that, when added back to the mutant yeast strains, restored their ability to grow on oleic acid. Today 23 of those genes are known to play a key role in forming a working peroxisome.

Not long after Kunau's discovery, geneticist David Valle, a former HHMI investigator at Johns Hopkins University, was editing a book chapter on peroxisomes. He spoke extensively with Hugo Moser and became fascinated with the organelle. It was the early 1990s, and Hugo and Ann Moser had already amassed and characterized a collection of cultured skin cells from hundreds of patients with ALD and other hereditary peroxisomal diseases. In cells from less severely afflicted patients, intact peroxisomes could be observed by treating cells with antibodies to the peroxisome surface; subsequent biochemical tests on the cells revealed a single defective peroxisomal enzyme. In cells from the sickest patients, however, the researchers saw peroxisome ghosts—empty sacs with none of the enzymes the organelle usually contained.

Valle's team, including then-postdoc Jutta Gärtner, began working with the Mosers and a Hopkins colleague, Stephen Gould, to identify the genes that go awry in the sickest group of patients.

Photo: Fred D. Mast / Rachubinski Lab

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