"In the days of the Chinese emperors," recalled molecular geneticist Richard Swank, "people collected fancy coat-colored mice." He does the same in his spacious mouse laboratory at Roswell Park Cancer Institute in Buffalo, N.Y. His purpose is not aesthetic but biologic.
Recently, Swank and his colleagues "spent two summers at the Jackson Laboratories in Bar Harbor, Maine. There we went through their enormous collection of naturally hypopigmentation mutant mice, looking for coat-color mutants. The lab made available for us 47 such mutants, which we went through systematically, looking for defects in bleeding.
"Unremitting bleeding," Swank pointed out, "is a major hallmark of a rare congenital disease called Hermansky-Pudlak syndrome [HPS]. Drs. Hermansky and Pudlak," he noted, "were two Czechoslovak physicians who back in 1959 published the first account of HPS in the journal Blood. Its title told the first grim story of this adjective-defying malady: "Albinism associated with hemorrhagic diathesis and unusual pigmented reticular cells in the bone marrow: Report of two cases with histochemical studies."
That was then. Now, Swank is senior author of an article in Nature Genetics, released online Aug. 17, 2003, and titled "Hermansky-Pudlak syndrome type 7 (HPS-7) results from mutant dysbindin, a member of the biogenesis of lysosome-related organelles complex 1 (BLOC-1)."
"That particular article," Swank observed, "reported the positional cloning of one HPS gene in a mouse model. It turned out to encode a protein that other labs have implicated in the dystrophin-related protein complex [DPC] in muscle cells, which is completely unexpected."
Bleeding At Birth; Lethal Lung At Midlife
"In humans," Swank told BioWorld Today, "Hermansky-Pudlak syndrome is a rare disease to be sure, but deadly for those who have it. Its two main clinical symptoms are prolonged internal bleeding and fibrotic lung disease. People have died of the disease," he continued, "because of abnormalities in the function of an organelle within platelet-dense granules.
"Fibrotic lung disease," he went on, "is even more lethal. Its basis has only begun to be understood. It's the lamellar body of two cells within lungs. Normally the lamellar body there serves as a storage site for lung surfactant. This is critical to be secreted into the pulmonary space. Otherwise, the HPS patient literally can't breathe. That's what happens to these HPS sufferers, not immediately, but in midlife, when it's a gradually clinical-appearing symptom. Usually in the mid-30s they develop the lung symptom, and within two or three years they're dead. It's even more deadly than bleeding.
"The bleeding symptom appears almost at birth. I know of one mother," Swank recounted, "whose 11-year-old daughter has been to the emergency room 50 or 60 times, owing to this recurrent crisis. They're thinking of doing bone marrow transplantation to ameliorate the condition. There's no good treatment at present, just symptomatic counsels like Stay out of the sun' because ultraviolet light aggravates HPS's albino pigmentation, and Avoid aspirin' because of its bleeding propensity.
"As for HPS's epidemiology," Swank went on, "there are an estimated 800 to 1,000 patients identified worldwide. But its incidence is probably underrated and gets misreported as some other bleeding disease. An HPS patient network came into being in the last five to seven years. It started off with 50 unknown patients. Then many went on radio and TV and advertised the symptoms to a wider market, especially in the New York City area. They found that it's prevalent in Puerto Rican patients.
"The NIH has established a founder effect. They posit that in the 1600s a Spaniard came over to the New World and carried the disease with no thought on inbreeding. He settled in the northwest part of Puerto Rico, and there are at least 400 HPS patients in that part of the island to this day. There is some inbreeding, and as HPS is recessively inherited, you need some intermarriage for it to spread. So usually it's consanguinity of parents. By chance couples mate and each parent may have an abnormality in the same gene.
"But now it's found throughout the world - more than 50 countries at last count."
Three Therapeutic Goals, One Research Plan
Swank and his team are now pursuing ongoing research with a single goal: "It would be really nice to have some kind of therapy for those HPS patients. It's still a little pie in the sky," he mused, "but we're hoping that gene therapy may work in the lung by putting in a good copy of the gene intranasally via nebulizer or aerosol and allowing patients to inhale it, which would correct the defect. But this is a long way in the future yet.
"Stem cell therapy might perhaps be a little bit further in the future," he added. "Not only are we identifying the genes, but we'll be able to tease out features of them that will allow some drug to be designed."
On this score, an issue arises as regards an orphan disease such as Hermansky-Pudlak syndrome. Major pharmaceutical companies will be loath to invest in such orphan diseases with limited markets.
"In addition to those three kinds of clinical approaches to try to aid the patients," he summed up, "we are all at the basic cell biology level - just to understand how to make these organelles. Now we have at hand nine completely new genes that have novel functions. Sooner or later, we and/or others are going to tease out what they do in molecular and cell biological terms," he concluded. "How do they make these organelles?"