Adjunct Assistant Professor, Department of Biology, University of Victoria
Staff Scientist, UCSF Benioff Children’s Hospital Oakland
Research Areas: genetic anemias, iron overload, neurodegeneration with brain iron accumulation (NBIA), Mucopolysaccharidosis, mitochondrial function, DNA damage
It is one of the most abundant elements on Earth. A soft, grayish metal that (as an ion) acts as a shuttle in the human body, working to deliver the oxygen and transfer the electrons required to power our cells. The average adult has just 3 to 4 grams of it — about the weight of a single nickel — distributed throughout the body.
“Iron is a very precious commodity,” says Dr. Patrick Walter, an adjunct professor at the University of Victoria and a staff scientist at the UCSF Benioff Children’s Hospital in Oakland, California.
So valuable in fact, that our bodies have evolved to cling to the limited amount of iron that we are capable of absorbing from our food. Most people are aware of the consequences of having too little iron, but what happens if we have too much?
This is exactly what Walter, who studies iron overload in children and adults, is working to better understand. Walter, who has a doctorate in biochemistry, is currently conducting research projects in three main areas.
Genetic Anemias. Walter is focusing on thalassemia and sickle cell disease, both genetic disorders in which the body makes abnormal forms of hemoglobin — the iron-containing protein in red blood cells — that impairs the body’s ability to produce red blood cells. The frequent blood transfusions that are required to treat these conditions lead to an overload of iron in these patients. Excess iron creates free radicals that damage cells throughout the body, resulting in fatigue, joint and muscle pain, and even permanent organ damage.
The only way to remove the excess iron is with chelation agents, small molecules that bind to iron and are then excreted through bile and urine. Unfortunately, traditional chelation therapy (CT) requires regular injections and comes with a host of side effects that make adherence to treatment an ongoing challenge.
Walter is studying the effectiveness of CT and is looking at the potential for less cumbersome and more effective combination therapies. He has already played a role in getting a new drug to market, Defarasirox, the first widely available oral chelator in North America.
Walter is also trying to figure out why some individuals are more prone to iron overload in certain organs, particularly the heart, pancreas, and brain.
While a small amount of iron buildup in the liver is natural — in fact, iron concentration in healthy individuals is an excellent indicator of age, much like the rings in a tree — iron overload in the heart muscle can cause a devastating loss of force (and often death) within just 18 months of CT treatment cessation.
Neurodegeneration with Brain Iron Accumulation (NBIA). In addition to his work in hematology, Walter is conducting research in the field of neurodegeneration. He is studying a rare, pediatric, genetic, neurodegenerative disease that leads to iron overload in the brain and is associated with an early-onset progressive movement disorder, very similar to Parkinson’s disease.
Walter is looking at why iron is accumulating within the brain. He is involved in a worldwide CT trial with a research consortium, Treat Iron-Related Childhood-Onset Neurodegeneration (TIRCON), that is studying the genetic mutations behind the disease and testing the efficacy of CT in preventing, and potentially reversing, brain iron overload.
Mucopolysaccharidosis. Walter has also taken an interest in mucopolysaccharidosis (MPS), a type of lysosomal storage disease that has a similarity to iron overload disease because both excess iron and polysaccharide are stored in the lysosome. Specifically, he is focusing on the faulty (mutated) enzyme inherent in MPS type IVA, a disease in which faulty and misshaped enzymes are unable to breakdown key polysaccharides leading to their accumulation within the lysosome of cells.
Walter is taking two approaches to restore enzyme function in MPS IVA. Primarily, he is researching the efficacy of enzyme chaperone therapy, testing out small molecules, which attach to the faulty enzymes and restore their shape and function.
Secondly, he is working on promoting an ideal cellular redox environment — one that is geared towards stabilizing and maintaining the molecular bonding that is key to the quaternary structure of the enzymes.
Ultimately, Walter’s goal is to understand the key mechanisms involved in these diseases in order to improve patient quality of life. He hopes to devise novel ways of uncovering disease mechanisms, continue improving CT, develop better neutraceutical and antioxidant combinations, and pin down the ideal dosing requirements.
“That is always a good feeling to help…to get a drug to market that is going to be effective,” says Walter.
Walter is grateful for the opportunity he has been given to collaborate with other members of the CBR, including work done on: genetic anemias with Dr. Perry Howard and Dr. Terry Pearson; NBIA with Dr. Patrick MacLeod, Dr. Christoph Borchers and Dr. Raad Nashmi; and MPS with Dr. Francis Choy.