Decoded Dog

by Dianne Janczewski

  We owe dogs a bath. While there is nothing happier than a muddy dog, we have created coats that are like Velcro for dirt and burrs, and we have essentially erased grooming behavior critical to keep them sufficiently coiffed; though curiously it is retained in cats. Wild canids—wolves, foxes, maned wolves, dingoes—all thirty-four species, may be found with tiny flora and fauna making a home imbedded in the animal’s fur, but for the most part canids keep themselves clean and beautifully groomed. They depend on growing and shedding undercoats, to keep them warm and cool, and even to communicate, raising their hackles to show aggression. Dogs wouldn’t be caught dead, or rather would be dead, without a well-cared-for coat. Mine don’t know the art of grooming other than the slicker brush that strokes them to sleep in front of the TV. Rarely do they wash the day from even their paws. I think the flavor of dirt is distasteful to them.

  We owe dogs veterinary medicine. We owe them vaccinations against disease, treatments for parasites, and a mess of other preventatives, therapies, and cures. After all, we traded their genetic diversity for short-muzzled, wrinkly-faced curly-tailed pugs, lean-legged greyhounds, and wrinkled shar-peis. We have bred into them expressed traits—phenotypes—that make us happy, and we have bred out of them unknown genes that could have been advantageous when facing emerging diseases. As they are our closest buddies, it makes sense that we have created in them a situation no different from what we have created in our own species. The paradox of the benefits of modern medicine, veterinary medicine included, is survival of the not-so-fittest. Take hemophilia for example; modern medicine facilitates the survival of individuals with this disease, and thus the retention of these deleterious genes in the species. Through selective breeding to create the domestic dog, much like with ourselves, we eliminated the naturally-occurring species.

  Make no mistake, there is still a lot of genetic diversity in the domestic dog. A study that compared thirty breeds living the comfy life, dogs from African shelters that had been freely outbreeding for generations, and other members of the Canidae (wolves, jackals, and coyotes) found a remarkable amount of genetic diversity, or heterozygosity, particularly for large gene complexes that code for body size and shape and for hair and pigmentation traits. The effect of domestication and artificial selection on the dog is a dominance of a few genes with a large effect. In another study of genetic diseases in 114,000 domestic dogs, surprisingly only three breeds—the bull terrier, miniature bull terrier, and boxer—were found to have a low heterozygosity.

  Yes, we have narrowed the gene pool in the population, and clearly some breeds suffer because of it, routinely requiring interventions like C-sections or operations to correct eye and nasal issues, all due to the look we have created. A recent study looking at dogs’ medical records indicated that for the majority of diseases, there was no significant difference between purebred and mixed breed in the prevalence of disease. The few diseases that did show a difference were found more often in purebreds. These could and should be removed from the breeding population.

  So, we also owe dogs ethical breeding. We owe them genetic testing of potential parents to avoid passing on genes for diseases like degenerative myelopathy, progressive retinal atrophy, and von Willebrand’s disease. We owe them evaluation of the structure of their hips to avoid perpetuating crippling hip dysplasia, and we owe them decisions on what animals to breed based on hard science.

  The concept of “outbreeding” the domestic dog to improve the gene pool is not scientifically supported, and in fact it can cause additional complications. One can easily imagine that crossing a Chihuahua and Great Dane would more than likely create a combination of body structures that would be debilitating for the offspring. While it is not as obvious, there can be similar problems when crossing poodles and Labrador retrievers or Australian shepherds, which are all built very differently both physically—for example, in the placement of the legs and carriage of the chest—and behaviorally, with distinct differences in their retrieving and herding instincts. These differences may be subtle, but the resulting offspring can be unbalanced in their structure and their behavior. The road we have journeyed with dogs is well travelled. We owe them our careful consideration of what we allow to pass on to future generations of puppies and companions.

  Sometimes I do feel sorry for my dogs as they spend their days curled in slumber with nothing to do but wait for me to play with them, feed them, connect with them. But they sleep contentedly, which is a valuable gift.

  “It’s really quite elegant.”

  “Elegant?” Jamie scoffed from the other side of the bench. His black-and-white view of science leaves no room for modifiers like elegant, intriguing, or fascinating—though I have heard him mumble an occasional “Cool.”

  Ignoring him, I turned back to Haley and the white board. Having worked for these few weeks in an Addison’s research lab she has absorbed some understanding of the disease progression and mechanisms of the adrenal system, but inserting the effect of CRFS introduced a whole new layer of complexity. “Yes, finely balanced and simple or elegant.”

  “Geez I can’t keep any of this straight,” Haley said.

  “Let me draw it out for you. There are three areas in the body that are involved: The hypothalamus region in the brain, pituitary gland at the base of the brain, and adrenal glands on the kidneys. These three talk to each other through chemical and electronic pathways.” I did my best to sketch them on the board.

  “When an animal gets stressed—and stress can come in a lot of forms like immediate fear or excitement, or slow-rising anxiety—”

  “Like a semester-long paper,” Haley said.

  “Or a charging pack of Chihuahuas,” Jamie teased.

  I ignored them and continued, “Stress triggers the hypothalamus to release the chemical CRH or corticotropin-releasing hormone.” I drew a red stress arrow and a blue CRH flow arrow. “CRH then triggers the pituitary to release ACTH or adrenocorticotropic hormone.”

  “I’ll never remember these names.”

  “You will eventually. For now, concentrate on the organs and acronyms.” I drew arrows to the adrenal glands on top of the kidneys. “Finally, ACTH triggers the adrenals to release cortisol.”

  “And cortisol is the Chicken Little of the stress response, running all over the place and causing everyone to get excited,” Jamie said, flailing his hands in the air.

  Megan joined him, throwing her hands in the air and swaying round and round for a moment. As she dropped her arms to her lap, she said, “That is, as long as there is enough glucocorticoid receptor or GR to go around.” I wrote that one on the board.

  Jamie took the ball and continued. “Yeah, cortisol is carried by the blood all over the body but it can’t do anything at the cellular level until it binds to GR inside the cell. Once the two bind together they enter the nucleus and trigger the stress response activity.” He hiked an imaginary ball to Me.

  “Yup,” I said. “Once in the nucleus it triggers gene transcription, resulting in lots of stress reacting proteins.”

  “That’s neat.” Haley was clearly amused by them.

  “Yes, very neat,” I said. “About the cortisol, but also how you two can still get excited about explaining the process.” The co-conspirators, proud of their performance, returned to their work, allowing me to continue my lecture to my audience of one. “Actually, there are all kinds of other chemicals and pathways that are triggered, like adrenaline, but cortisol starts the biggest cascade of responses.”

  “Got it.” Haley studied the board locking it all in.

  “So, what do you think happens when the stress goes away? Do you think the body still needs to keep the system turned up to full speed, sending cortisol all over the place, keeping the heart racing, keeping the muscles contracted and ready for flight?”

  “No. So I guess somehow the system knows when it’s produced enough cortisol?”

  “Bingo. Cortisol’s binding to GR also serves as a built-in feedback mechanism to help
the system return to normal. As we said, cortisol goes all over the body connecting with GR in each cell and activating stress responses. But when all the GR is bound up and can’t take on any more cortisol, the cortisol levels start to increase in the blood. The hypothalamus is sensitive to this, and shuts down the release of CRH and the whole cascade of responses stops.”

  “That makes sense.”

  “Exactly. There is only a set amount of GR in a cell, and once it gets bound by cortisol, no additional cortisol gets in.”

  “So no more GR, cortisol builds up, and feedback to the hypothalamus turns off the system,” Haley said.

  “Correct. This is an oversimplification because, like I said, there are a bunch of other reactions going on. But this is the biggest part of the delicate balancing act.”

  “It’s all so elegant,” Jamie said, holding a beaker like a tea cup, his pinky extended.

  “And you all are thinking that somehow CRFS has an impact on the GR gene, causing it to what? Become turned on, making more GR and messing up the feedback loop?” Haley asked.

  “Yes!” I responded, pleased that she’d worked it out. “Like I said, each cell makes and has ready a set amount of GR, and when it binds to cortisol, it’s unavailable to pick up more, setting a maximum limit of cortisol-activated activity. You don’t see an increase in GR production as a response to stress, as it is part of the regulation of the response. But in dogs with CRFS, something is telling the cells to produce more GR, and with more available, it keeps activating cortisol all over the body, and the whole system goes out of whack. Tissues and organs are thrown into overdrive and quickly start to fail.”

  “Okay, I think I get it. Too much GR means the cortisol keeps getting removed from the blood and the system doesn’t sense cortisol is at maximum acceptable levels and should shut down.”

  “Correct. So, in the normal dogs that get CRFS the adrenals start to fall apart from the constant surge of ACTH and over-activity to produce more cortisol, then the rest of the cells in the various organs start to fail.”

  “And the Addison’s dogs?”

  “There aren’t functioning adrenal glands to receive the ACTH and produce cortisol. Instead, there is a constant level of cortisol-like steroids that are part of the medications they receive, that keeps them at a steady state of low-level response.”

  “Doesn’t the constant level of cortisol hurt them?”

  “No. It is a very low level compared to actual stress levels, but without the adrenals they are not able to respond well to stress. That’s why we call them soft dogs, because they fold into themselves in stressful situations. They are unable to take it.”

  “Poor things,” Haley said.

  “Not completely. It makes them really cuddly companions, and with medication and proper care, they can thrive. But with respect to CRFS, since there is nothing to keep producing cortisol, extra GR in the system doesn’t do anything initially.”

  “So what happens eventually?”

  “Well, eventually the extra GR takes up all the cortisol that is there from the medication and with nothing left, they fall into a typical Addison’s crash.”

  “But why do Addison’s dogs with CRFS have a higher increase in the GR gene? You said that, right?” asked Haley.

  “I’m thinking that since they are slower to respond to CRFS—that their system simply has a little more time to overproduce GR before they collapse.”

  I turned to Megan and Jamie. “That reminds me you guys, we need to ask Anna if she’s seen any difference in the rate of disease progression between the Addison’s dogs that receive monthly hormone/daily prednisone injections versus those who are treated with that uber-expensive daily fludrocortisone acetate oral treatment. Does she even have any of those?” Jamie and Megan looked at each other then looked at me. “I take it I don’t have to ask her. You guys already know the answer.”

  “Yes! I mean, no, you don’t need to ask. We already have that information on the samples!” Megan said, rapidly leafing through papers and scanning for the correct data. “We saw two different levels of increased mRNA but thought maybe it was a time of day thing since the whole HPA system works on a circadian rhythm.” She opened the binders and pulled out a page, smacked it on the lab bench, and motioned me over. “Here they are! See? These eight dog samples show a slightly higher level than the other forty-three. And I can easily cross check them back to the prescription data that we have for all of the Addison’s dogs!”

  “I’m betting the data will match perfectly to disease progression, with the ones that get daily treatment holding steady longer than the ones that get a monthly injection,” I said. “This won’t tell us anything new but will at confirm again of our theory on the mechanism of how CRFS attacks the body.”

  “And will add credibility for a really cool paper?”

  Our heads all snapped in Jamie’s direction.

  I smiled. “It’s okay, you can think like that, but only after your comment about how it moves us one step closer to saving a lot of dogs.”

  “Of course, I meant that! It was implied since I’m such a dog lover.”

  We all groaned and settled in to our own thoughts on the work ahead.

  Sure enough, dogs getting daily meds were less affected initially and had the highest levels of GR, which made sense since those receiving monthly meds could be anywhere in the cycle: having just received their dose or being close to needing it. Still despite all our efforts, despite knowing what the symptoms were at the biochemical and molecular level, we still couldn’t figure out the cause. The levels of GR were increasing, causing the body to quickly shut down as the feedback mechanisms that regulate the system faltered. But what was causing the increase?

  We knew we were looking for something that was kicking the GR gene into high gear. The next step was to look at the DNA sequence that codes for the mRNA to see if anything was anything was wrong with it. We pulled out the corresponding DNA fragment, including pieces on either side of the gene to determine whether something was wrong with the promoter—the tiny sequence prior to the gene that regulates production—or the stop codon that indicates the end of the gene.

  By the day before the university’s spring break, we still had nothing.

  OUT OF THE MOUTHS OF BABES

  I AM a dog person. Of course, that’s what my dogs would claim too. And though they are happy to believe this since they are treated like members of the family, I am not one of those people who says that my dogs are my children. Not because I have children, but because I think we do animals a disservice when we anthropomorphize them too much instead of appreciating their uniqueness as totally different species. We marvel at discoveries of how whales communicate through song or how other primates use tools. Yet right under our own roof, we are granted insight into the innermost secrets of the dog and its instincts—and we too often feel compelled to see them in the context of our species. We want to tuck them in the same pocket of our heart where we place kids, when dogs belong in their own space. While I often fail, I try to keep them separate. In some odd way it helps me to accept when they die that their place is different and their time with us was always destined to be shorter. I love my children and I love my dogs, but differently. And that is what makes dogs all the more special.

  Diana’s cough was persistent. Annoyingly persistent. I had to check myself. My personal stresses were overriding the empathy I was supposed to feel as her mother. Sometimes I’m just not that good of a person. My daughter had a cold—worse than that: a sore throat and a fever that challenged me to time perfectly the alternating doses of ibuprofen and acetaminophen, lest her temperature skyrocket towards 103 and we have to bring in a different kind of doctor. Having already coaxed her to school for the first two days of her illness (knowingly exposing her classmates for my own selfish reasons), I realized I should assume the role of full-time mother, so I nestled her in a stack of pillows and blankets in the living room where she could drift in and out of sleep and SpongeBob’
s pineapple world under the sea. The day also brought over-salted chicken noodle soup and warm milk with honey and butter, in the tradition of generations of my maternal ancestors.

  Lucky for Diana, this was not her spring break. Unfortunately for me, it was mine at the university.

  Ania, sensing the need for her nursing abilities and finally seeing an opening, she stepped up to take her place at Diana’s feet.

  “No, Ania, you go sleep over there on the floor,” she said, shoving her feet to block the open space.

  “What’s up, you don’t want her next to you?” I asked. “She probably senses you’re out of sorts and wants to help.”

  “I know. I want to cuddle with her too, but I don’t want her to get my cold.”

  “Dogs don’t get human colds,” I said, as I motioned to Diana to scrunch up. I patted the couch to invite Ania to the claim her spot.

  “Why?”—she must have sensed the inevitable science lecture coming—“The short version please. I’m sick. Remember?”

  “Well, the Reader’s Digest version is that different species are susceptible to different viruses. Since different cell types of different species each have different receptors—those little proteins on the surface—viruses can only connect to and invade those cells that have receptors that fit, so they’re species-specific.”

  “Oh yeah, I remember you told me before that fish can’t get rabies, but all mammals can.”

  “Yup.”