Medicine: Treat Today, Cure Tomorrow
At Hadassah’s Center for Metabolic Diseases, mutations in DNA are researched and identified, paving the way for a future free of gene-based illnesses.
A 9-day-old baby girl is brought to the Hadassah–Hebrew University Medical Center at Ein Kerem; she is lethargic and unresponsive. It is quickly established that the ammonia level in her blood is 14 times higher than it should be. Her parents are closely related to each other and have already lost two babies in their first week of life.
An angry, red-faced woman forces her way into the office of Hadassah pediatrician Orly Elpeleg, clutching her 8-month-old son. “Look at him!” she shouts. “He can’t see anymore, he can’t hear anymore, just like his sister! You’ve got to help me!” She collapses in convulsive sobbing.
A 2-day-old baby is failing, already deep in coma. He is unlikely to survive, but Hadassah’s specialized lab is rushing tests. Perhaps they can save him. If they can’t, their findings may save future babies born to his grieving young parents.
Sometimes our work is almost intolerably tragic,” says Dr. Elpeleg, an internationally known expert in metabolic diseases and director of Hadassah’s Center for Metabolic Diseases. “While the technology that will replace faulty genes and heal these children is on its way, it isn’t here yet. Meanwhile, although we can’t cure, we can help many young patients survive and lead normal lives, especially if they’re brought to us early. And we’re laying the groundwork for the medical future.”
Dr. Elpeleg came to Hadassah, her alma mater, two years ago to head this cutting-edge center. She is working with a dozen physicians and scientists to track the thousands of metabolic diseases that damage, maim and kill—identifying, diagnosing and researching them and, wherever possible, treating them.
“Metabolic diseases are the broad range of medical problems caused by inherited mistakes in the genetic code, which disrupts the body’s metabolism—the process by which it turns food into energy,” she explains.
This process is zealously orchestrated by the more than 2,700 chemicals called enzymes. Enzymes convert digested food into substances that the body’s cells can absorb for energy, build essential compounds unattainable from diet and break down no-longer-needed matter into waste products. In metabolic diseases, either a vital enzyme is not produced at all or too little of it is produced. The substance that the enzyme is designed to process (a sugar, protein or fat) therefore remains unmetabolized. Over time, it accumulates in body tissues or major organs, building to fatally toxic levels.
“The type and degree of damage depends on the enzyme affected,” says Dr. Elpeleg. “Impairment can range from mild, relatively harmless symptoms not even recognized as disease to abnormal movements, stunted growth, severe developmental delay, mental retardation, brain seizures and early death.”
Among better-known metabolic disorders are Tay-Sachs and Wilson’s diseases, leukodystrophies (such as Canavan disease), lysosomal disorders (among them Fabrys and Gaucher diseases and Hunter syndrome) and phenylketonuria (PKU).
Although there are thousands of metabolic disorders, all are rare, cumulatively affecting on average one in every 4,000 people worldwide. In Israel, however, where marrying blood relatives is comparatively widespread among both Jews and Arabs, its incidence is probably higher. This keeps Hadassah’s National Center for Metabolic Diseases busy.
Upgraded two years ago from a unit, the center is now housed in custom-built premises on the third floor of Hadassah’s Ein Kerem campus, furnished with state-of-the-art equipment and laboratories (metabolite, enzymological and molecular) and staffed with leading clinical and research physicians and scientists. It is located a revolving door away from the Hadassah–Hebrew University Medical School, whose researchers the center works with closely.
“Metabolic disorders are at the interface of clinical medicine, biochemistry and molecular biology,” says Dr. Elpeleg. “Our multidisciplinary team, with its daily interaction between clinical and basic research, is one of our strengths. This, along with sophisticated equipment acquired late last year, enables us not only to identify missing enzymes and pinpoint accruals of unmetabolized substances but to investigate their genetics as well. That is, we’ve progressed from studying larger complex compounds to the tiny DNA molecules themselves—the final step in genetic diagnostics.”
As the only place in the Middle East addressing the whole range of metabolic disease, the center has patients from all over Israel and the Palestinian territories as well as from surrounding countries. The frantic mother of the blind and deaf 8-month-old, for example, had given birth to all her children at another hospital, but then sought help at Hadassah.
“This unlucky woman believed the vegetative state of her eldest child, now 7, had resulted from a birth accident,” says Dr. Elpeleg. “Her certainty grew when her next two children were born healthy. But when this 4th child went into the same decline as her first, she turned to us.”
Too late to help the mother’s affected children, Hadassah looked for what had gone wrong. Although both parents are of Iranian Jewish descent, they were not, to their knowledge, related. Testing, however, showed that both carry copies of a genetic misprint that eliminates production of a key enzyme—bestowing a grim one in four chance that any child born to them will suffer devastating neurodegenerative illness.
“With today’s capabilities, genetic diagnosis can do no more than help this couple accept their tragedy,” says Dr. Elpeleg. “In the future, when replacement of faulty genes becomes possible, I believe it will be the foundation of a cure.”
However, many of these disorders can be held at bay for a lifetime by special diet, vitamins or supplements. The news for the unresponsive 9-day-old girl, for example, is good. A sophisticated metabolic workup found that the amino acid ornithine is accumulating because she lacks the enzyme that should dispatch it to her mitochondria. She was given a replacement enzyme, and within a day her ammonia level was normal. She will take this supplement daily as long as she lives—or until gene therapy becomes reality—making her illness mild enough to allow her a normal life.
“Rapid diagnosis is the key to helping these children,” says Dr. Elpeleg. “Over time, the buildup turns toxic and wreaks irreversible damage.”
This need for speed is a major stumbling block in treating metabolic diseases. While there is automatic screening for some in most Western countries (PKU is one), metabolic testing is generally too lengthy, costly and imperfect for blanket screening.
“Medical science has recognized the existence of metabolic diseases for half a century, but the tools to study and combat them have existed for less than two decades,” says Dr. Elpeleg. “Until very recently, the best screening method was chromatographic separation of the blood and urine. But with at least three hours needed to prepare each sample and the system inapplicable to many compounds, it’s an inadequate tool.”
In November 2006, Hadassah’s Center for Metabolic Diseases took a diagnostic step forward with the arrival of a $300,000 tandem mass spectrometer. “This spectrometer can identify more than 20 metabolic problems in a one-minute test on a single drop of blood,” says Dr. Elpeleg. “It’s the very best there is and the only one in any Israeli hospital.”
Analysis and interpretation of the clinical data produced by the spectrometer requires significant expertise. Hadassah pediatrician Stanley Korman spent a year in Australia training in its use, among other things. (So specific in identifying certain compounds and so accurate in measuring minute amounts of material, it is also much valued by forensic police.)
“We’d been hoping to acquire a tandem mass spectrometer for several years,” says Dr. Korman. “The day after I left for my sabbatical year, Hadassah finally found a donor…. It’s very exciting to operate, because it’s so rapid and so sensitive. Most of my learning curve, however, was devoted to interpreting the results.”
The mass spectrometer is not the center’s only new technology. It has also recently taken delivery of a DNA sequencer, an instrument that can read 3,000 nucleotides (DNA building blocks) in a single hour. Given four days, it can examine the entire genome. The Hadassah team is using it to find faulty gene fragments identical in both parents of sick children.
“With this DNA sequencer, we add study of the genetics of these diseases to their diagnostic, clinical and metabolic facets,” says Dr. Elpeleg. “We’re also able to assemble thousands of samples for research, which we expect to underpin future cures.”
Research at the center has already identified mutations associated with Canavan disease in Jewish Israelis as well as nine new Canavan mutations among European patients of non-Jewish ancestry. They have analyzed the molecular basis of a neurodegenerative disease of early childhood (glutaric aciduria type 1) in Israeli patients. Dr. Elpeleg has diagnosed the disease among Jewish and Muslim communities in Israel and learned it is caused by seven newly found mutations.
And they are investigating the basic defects in a new group of mitochondrial respiratory chain defects, which they believe account for almost 5 percent of patients with these disorders. Five mutated genes have been identified and the resulting illnesses described, establishing a new concept in mitochondrial medicine.
“While the treatments we can offer are still limited, they are saving more and more patients,” says Dr. Elpeleg. “At the same time, we’re building a vast databank for a future in which we expect that defective gene fragments will be replaced, curing these diseases altogether.”
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