by Marcia Hill Gossard '99, '04
(l-r) Nicolas Villarino, WSU assistant professor; Katrina Mealey, WSU professor and Richard L. Ott Endowed Chair; Michael Court, WSU professor and William R. Jones Endowed Chair
Carlee, a 7-year-old yellow lab, is a mutant. Like many of her human redheaded counterparts, Carlee has a mutation in the MC1-R gene, or melanocortin 1 receptor. The gene is responsible for producing melanin, a pigment that determines hair, or in this case, coat color. Because humans with red hair often have a lower threshold for thermal pain, researchers at the WSU College of Veterinary Medicine wondered if they would find similar results in Labradors.
Dr. Stephen Greene, WSU veterinary anesthesiologist, and Dr. Tania Perez, PhD student and clinical instructor, recruited 31 Labradors—black, chocolate, and yellow—for the study. After taking a cheek swab to test their genetic makeup, they observed the dogs’ reaction to mild heat and pressure by attaching special equipment to the dogs’ front legs.
Tania Perez is testing to see when Carlee, a 7-year-old yellow lab,
will respond to a pressure point in her front leg.
“With the devices, we can measure the precise amount of pressure or heat the dog is receiving,” says Greene.
When the dogs feel the sensation, some pull their leg back, look at it, or start licking it, says Perez. When they see the reaction, the researchers record the temperature or level of pressure. They repeated the experiment several times and took an average to be confident the measurement was accurate. But the results were not what they expected.
“We thought we’d find difference in thermal tolerance,” says Greene. But they found no difference between the dogs. Instead they found that when they compared yellow and chocolate labs that carry the mutant gene to black labs that don’t carry the gene, there was a significant difference in how they responded to pressure. Based on this research, veterinarians may be more likely to give additional pain medication after surgery when treating a yellow or chocolate lab with this genetic mutation if the animal seems distressed, since it is likely the animal also has a higher sensitivity to pain.
“Not all animals in the same breed will respond to drugs in the same way and it is challenging to understand pain in animals since they cannot talk,” said Greene. “Knowing genetic differences for pain tolerance will be helpful in getting optimal treatment to the patients.”
This research is just some of the exiting work happening as part of the Program in Individualized Medicine, or PrIMe, at WSU—the only program of its kind in the world.
“Every healthcare specialty, whether is it in oncology, cardiology, neurology, or pain management, involves pharmacology,” says Katrina Mealey, a WSU veterinary pharmacologist. “Our work touches all patients.”
One of a Kind Patients
More than a decade ago when Dr. Mealey discovered a MDR-1 gene mutation, she answered scientifically what veterinarians had long observed in their own patients. Veterinarians knew some dogs with white paws had an adverse reaction to ivermectin, often prescribed to prevent heartworm disease. Dogs with this mutation, generally herding breeds, do not produce enough P-glycoprotein to effectively pump the drug out of the brain, which leads to toxicity and causes the nervous system to shut down.
But even within herding breeds, not all have the mutation. About 50 percent of Aussies do, while only approximately 10 percent of Old English Sheep dogs do. The only way to know for sure if a dog has the mutant MDR-1 gene is to have the dog tested.
Researchers in the individualized medicine program often start by looking at why a patient had an unusual response to a particular medication. Similar to dogs with white paws, veterinarians have known that some Greyhound or other sighthound breeds do not always wake up easily after general anesthesia, but no one really knew why.
Michael Court and Nicolas Villarino’s research will ultimately lead to the
development of genetic tests so a patient’s treatment can be individualized.
Michael Court, professor and pharmacologist who joined the individualized medicine program in 2012, directed his research to answer that question. He discovered that a metabolic genetic mutation causes them not to regain full consciousness very quickly.
“We are currently working to develop a test that can be offered to dog owners within the next 12 months,” says Court. Once a patient is identified as having the mutant gene, then veterinarians will be able to prescribe a different dosage of anesthesia.
And it’s not just dogs. They are also finding that cats are quite different in how they respond to medicine. “Cats are not little dogs,” says Court. “But there are few articles that evaluate how drug effectiveness or toxicity differs between species.”
Nicolas Villarino, assistant professor and pharmacologist who joined the program in 2014, is looking specifically at cats and drug toxicity. He uses metabolomics, or changes to metabolites in the body, to study drug effects at a molecular level. He is currently researching why cats are more susceptible to toxic reactions to NSAIDs, such as ibuprofen.
The speed a drug is metabolized in the animal also affects what dosage a patient might need. Dr. Court found that for cats, certain drugs leave the body more slowly, which means they may need a different dosage than prescribed for a dog of a similar size. And recently Dr. Mealey has discovered that cats are also affected by the MDR-1 mutation.
“It is very important to identify the specific characteristics of the patient to provide optimal treatment,” says Villarino. By knowing how drugs are metabolized, they can identify predispositions to serious side effects and recommend optimal dosages.
One of a Kind Medicine
Often called precision medicine, customizing health care to individual needs has been used for decades in human medicine. But in veterinary medicine it is relatively new. Because animals may respond differently to many types of medications, the pioneering research conducted at WSU will help veterinarians tailor their care by giving them more treatment options.
“A drug may work in some animals, but not others,” says Mealey. And sometimes a drug can be more effective if it is combined with other drugs. “We often think of drug interactions as harmful, but they can be beneficial.”
University’s DNA Bank
Three years ago, WSU veterinary researchers
began collecting DNA to help identify
genetic causes of disease and adverse drug
reactions. With owner permission, they take
a cheek swab of dogs and cats who come to
the WSU Veterinary Teaching Hospital for
care. Currently they have DNA from
approximately 4,000 dogs and 500 cats. WSU
veterinary scientists can use the DNA bank
to learn how genetic differences may affect
treatment. The goal is to develop genetic
tests to identify at-risk dogs and cats so that
selecting a drug or dosage can be tailored to
the individual patient.
The group is also currently working with a pharmaceutical company to change dosage levels on the label of a chemotherapy drug known to have adverse effects in some patients. “Roughly 90 percent of all drugs are prescribed with a fixed dose,” says Villarino. “By optimizing the dosage, we prevent or minimize adverse reactions, but the medication can still be effective.” Even a small change in recommended dosage can be beneficial for individual patients.
“Some drugs have a narrow therapeutic window,” says Mealey. “So the effective dose is not very different from the toxic dose.”
Dr. Court believes their research will one day lead to predicting the type of medicine or dosage levels needed for many commonly prescribed drugs based on an animal’s age, breed, sex, and biomarkers, such as metabolites or a patient’s genetics. The goal is to make what they learn from their research available to practitioners to be used in veterinary clinics and hospitals.
“Veterinarians have known that drugs cause reactions,” says Mealey. “Our work is answering the questions that veterinarians have had for a long time. We are bringing benchtop science to the clinical science that veterinarians use every day.”