A Consumer Health Interactive Radio piece by Laurie Udesky

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Laurie Udesky: Gaucher disease is a rare disorder that can affect anyone, but it's most prevalent among Jews of Central and Eastern European ancestry, known as Ashkenazi. In fact, Gaucher disease is the leading genetic disorder afflicting Ashkenazi Jews: About one in 450 has it. People who have the disease lack enough of an enzyme to break down a specific kind of fat molecule in the body. As a result they can suffer from anemia and persistent fatigue. They can also feel mild to debilitating pain from a build-up of fat cells, which can lead to brittle bones and swelling in the liver and spleen. The disease may also harm the lungs and kidneys.

Until the 1960s researchers had no idea what caused Gaucher. Today much of what is known about Gaucher and how to treat it is a result of five decades of research led by Dr. Roscoe Brady, an internationally acclaimed scientist whose pioneering work identified not only the cause of Gaucher, but how to diagnose and treat it. Dr. Brady is also credited with identifying the metabolic defects in Neimann-Pick, Fabry, Tay-Sachs disease, and other diseases that scientists call lysosomal storage disorders. He has won numerous awards for his work, and his discoveries have been described as "the biochemical Rosetta stone" by Chemical and Engineering News. Dr. Brady is scientist emeritus at the Developmental and Metabolic Neurology Branch of the National Institute of Neurological Disorders and Stroke, which is part of the National Institutes of Health.

I spoke to Dr. Brady at his office in Bethesda, Maryland about the investigations that led to his critically important discoveries and the implications of his findings for other diseases. I'm Laurie Udesky.

Udesky: In his office in a labyrinthine building of the National Institutes of Health, Dr. Roscoe Brady shows me photos of a 5-year-old boy with Gaucher before his first treatment for the disease. He's lying on an exam table and then standing facing the camera. The child has a riot of dark hair on his head and a protruding belly.

Dr. Roscoe Brady: His spleen should be under the left rib cage. It's all the way down into his abdomen, as you can see.

Udesky: Does he have pain?

Brady: Plenty of pain. He has pain in his spleen, in his bones, and in his liver. His liver -- it should be under the right rib cage. It's down almost two thirds of the way down the right side of his abdomen. He has easy bruising -- see the bruise on his arm? He has low blood platelets, so he's bruising easily. He's pale, anemic, [and has] low blood hemoglobin, and also at this age has bone damage.

Udesky: When Dr. Brady first began his research 50 years ago, children and adults with Gaucher symptoms often had grim futures. The only treatment at the time was having one's spleen removed, which for unknown reasons lessened symptoms for a while.

Brady: Then if you take the spleen out and the liver gets worse, and the bones get worse, they fracture their pelvis, their vertebrae, their femur, and everything else. Then they get wheelchair-bound or bed-bound with these fractures.

Udesky: As Dr. Brady would later discover, Gaucher disease is an example of what can go wrong when a microscopic part of a cell doesn't break down, or biodegrade, a specific fatty material. Gaucher disease is marked by an overabundance of glucocerebroside -- a type of lipid, or fat molecule.

Glucocerebroside is a key component of white blood cells. White blood cells normally circulate in the body for about a week. After that their components are broken down into lysosomes, which are small parts of cells that contain digestive enzymes. In Gaucher disease, however, a particular fat or lipid molecule simply piles up and wreaks havoc throughout the body of people with the disorder.

Brady: Their spleen would get bigger and bigger and bigger. These people can have a huge abdomen: they can hardly walk with the spleen and big liver in there

Udesky: Brady teamed up with an Israeli scientist, Dr. David Shapiro, to investigate why the body was storing so much of the fat molecule. The two scientists knew there was too much glucocerebroside in people with Gaucher, but at that point, they still didn't know why.

Brady: We didn't even know at the time these molecules could be biodegraded. We had no idea. Nobody had any idea. Nobody had any idea whether this was wrong material being made, too much of a minor component being made, or something wrong with the breakdown. Nobody even thought about the breakdown, because there were no metabolic studies on Gaucher disease.

Udesky: Then Brady and Shapiro developed a way to observe glucocerebroside in action. They knew that this particular fat molecule is made up of a long-chain fatty acid, a second kind of fat, and a molecule of glucose.

The scientists made the glucose portion of the glucocerebroside radioactive, so they could trace what might happen to it. Nobody knew at the time that these molecules could be broken down, explains Brady. What they found was astounding: Every tissue in the body had an enzyme that helped split off the glucose from the fat molecule, thus causing it to break down -- or biodegrade. They watched with growing excitement as the radioactive glucose split away.

Udesky: What were the implications of that finding?

Brady: Well, the implications were immediate: I have the enzyme now. I know there's an enzyme.

Udesky: The experiment showed that there was an enzyme called glucocerebrosidase that could break down the fat molecules piling up and wreaking havoc in the body of people with Gaucher. But what Dr. Brady and his colleague needed to find out was whether people with Gaucher had that enzyme, and if so, how well it worked.

So Dr. Brady and his colleagues compared the tissues from normal spleens and people with Gaucher disease. Among the most significant findings were that Gaucher patients were deficient in that very enzyme, the one that breaks down glucocerebroside.

Brady: We knew at that point the implications of this for many, many diseases -- not just Gaucher, and Neimann Pick, and Fabry, but Tay Sachs as well. We now could predict what the enzyme defects were in all of these conditions. It's all the same story: missing breakdown, catabolic enzyme. The enzyme isn't working as well as it should. And in many of these diseases the enzyme is actually zero.

Udesky: However, Dr. Brady and his team found that Gaucher patients did have some of the enzyme. It would prove crucial in developing a treatment for Gaucher that worked.

Brady: I thought in the Gaucher patients it would be zero. I thought they wouldn't have any of that glucose-splitting enzyme, but they do have some. It's much lower than normal. But thank goodness they do [have some residual enzyme]. This is very important when you think about putting enzyme into a patient, a protein enzyme into a patient to treat them. It's very nice if they already have some of the protein there, because then the body doesn't see it as a foreign protein going into them. So they're very lucky in that respect.

Udesky: With his discovery, Brady theorized that if his team could purify the enzyme and inject it into Gaucher patients, it might help them. That was in 1966.

Brady: It was a heretical idea at the time. Nobody thought about injecting enzymes into anybody. If I were going to do that, I wanted to use a human source of such an enzyme [rather than from another source such as an animal or plant].

Udesky: Brady and his team found the enzyme in placental tissue and after an elaborate process of purifying it, they were authorized to do a safety trial in 1973. Liver biopsies were done a day before and a day after the enzyme was injected into two Gaucher patients to see whether there were any changes in the excess levels of glucocerebroside in their livers.

Brady: The first was a 15-year-old boy, and he had about a 26 percent reduction of the lipid glucocerebroside in his second biopsy sample. We did it again with a woman in her very late 40s [who had stored up twice as much]. We gave her twice as much enzyme as the boy -- and again, a 26 percent reduction. It looked pretty good. But nobody believed me. Everybody said this is completely fallacious. But we knew that this was pretty outside the error of that detection system, where the [margin of] error was about 9 percent.

Udesky: Another positive result of this safety trial, explains Brady, was that the levels of glucocerebroside circulating in the blood of these two patients came down to normal. Even more promising, they remained normal in the blood for weeks after the one dose of the enzyme.

Brady: And I felt if we could get enough enzyme into these people [with Gaucher disease], we could probably really help them.

Udesky: It took nearly two decades and much more research from Brady and his team before the Food and Drug Administration approved enzyme replacement therapy in 1991. That was after a series of experiments that pinpointed the correct dosage of enzyme and after a pivotal clinical trial with 12 patients in 1991.

Brady: They all got better, everything good you could imagine happened to them. Their spleens got smaller. Their livers got smaller. The hemoglobin went up, the platelets went up, and their bones got better. And when we started this, we had no idea that we could reverse all these problems in these people. I thought perhaps if we could just hold them at a certain stage and prevent them from getting worse, we would be doing very good, but the reversal of all of those difficulties was absolutely phenomenal.

Udesky: Since then, patients with Gaucher have used enzyme replacement therapy, or ERT, to keep the disease in check, allowing them to lead normal, active lives.

Udesky: Do you remember the first time somebody described to you how they felt after you gave them ERT?

Brady: Of course I do. They're absolutely marvelous, just so grateful. You go to a meeting you're attending and they come up, hug you, kiss you. It's amazing, truly amazing.

Udesky: To show me how the therapy works, Dr. Brady revisits the photo of the little boy with the protruding belly. First he holds up the photos of the boy prior to treatment:

Brady: Now I'll show you pictures of the kid -- remember the kid with the big spleen, the 5-year-old? This was his spleen. It's supposed to be up here under his rib cage. It's all the way down here in his abdomen going across into the pelvis. It should only be up here, same with the liver.

Udesky: Now Dr. Brady points to the photos of the boy after three years of enzyme replacement therapy. The difference is striking.

Brady: [After] three years the spleen now is one third the size it was. Here are his bones before enzyme -- thin, undermineralized, cancellous bone. Three years later this bone looks very normal on his x-ray. How about the boy himself? Here he is at age 8: maybe [there's] a little liver spleen enlargement. Look at him at age 13, no liver and spleen enlargement -- a perfectly healthy kid. How about at 20? He goes to college, meets this girl, gets engaged, and at 22 [has a perfectly normal child]. And at 24, he has another child. Great story.

Udesky: Now in his eighties, Dr. Brady continues to do research on Gaucher, and he's also involved in studies on Fabry disease and other lysosomal storage disorders.

For Consumer Health Interactive, I'm Laurie Udesky

First published September 18, 2006
Last updated May 14, 2008
Copyright © 2006 Consumer Health Interactive