Dogs have a long history in research. From the 1600s, as our understanding of physiology began to accelerate, to modern day, as we progress in the age of genetics, dogs have played a vital role in shaping our understanding and developing new treatments for a wide range of diseases.
Dogs and humans share over 350 diseases. Studies have shown over and over, conserved biological pathways and common mutational drivers among the two species.
Practically speaking, a dog's size and lifespan are closer to humans than mice. This makes it easier to assess the long-term effects of a drug or vaccine. There is also no need to reinvent clinical tools such as imaging or surgical devices used in human medicine to conduct studies in dogs, and treatment response scales are more or less equivalent. Researchers can also take biopsies of canine tumours multiple times as treatment progresses, a valuable asset for long-term follow-up studies.
In 1889 Joseph von Mering and Oskar Minkowski showed that removing the pancreas from a dog produced diabetes.Nobel Prize the next year.
Ivan Pavlov’s experiments on the digestive systems of dogs provided the first detailed observations of how the digestive system worked. This was made possible through his surgical techniques that allowed him to observe the digestive processes while the animals were able to behave normally. This provided new insights that could not have been achieved previously when the dogs were killed during the study. Among his findings, Pavlov described the physiology of the salivary glands, the stomach and the intestines in detail. He showed that the digestive tract is influenced by the central nervous system in a complex manner, and that psychological process can influence the nature of the fluids secreted into the digestive tract. For this work, Pavlov was awarded a Nobel Prize in 1904.
Against a backdrop of widespread rickets among children in the population, Edward Mellanby discovered that a restricted diet of oats and being kept indoors resulted in rickets in dogs. Simply adding cod liver oil to their diet led to quick recovery. This is because rickets is caused by a deficiency in vitamin D, which had not been discovered at the time. We now know that the body creates vitamin D naturally when exposed to sunlight but can also be found in cod liver oil.
Multiple sclerosis (2021)
Granulomatous meningoencephalomyelitis, or GME, in dogs comes with Seizures, vision problems, sluggishness, a strange head tilt caused by hordes of immune cells swarming the brain much like a familiar condition in humans, multiple scelrosis (MS). According to a new study (2021) this most common neuroinflammatory canine disease, shares key features of its pathology and immunology with multiple sclerosis. Both GME and MS tend to affect females, and diagnoses are more common in those who are younger. In both diseases also, immune B cells, which usually make molecules that sound an alarm to the immune system, or pick up debris from bacteria or fungi to put other immune cells on their scent, gather in the layer surrounding the brain. No one knows exactly what they’re doing, but treatments that reduce B cells have been effective against some forms of MS. Researchers are eager to see what happens when dogs with GME are treated with the B cell-reducing drugs that some MS patients take.
Although MS and GME are not identical – the main hallmark of MS is the erosion of the protective coating around neurons, and that is only a side effect in GME – the comparison of both diseases could help treat both conditions. In particular, it could help improve early diagnosis of GME by using the spinal tap tests for MS. Follow-up studies have already shown that there are distinct molecular signatures of B cells in these dogs’ spinal fluid that could be a more accurate sign of GME. Inversely, if scientists find ways to target that inflammation in dogs, that could be translatable to humans with MS but also other inflammatory diseases.
Dogs could even be a better model of the disease than mice. Dog brains are bigger than mouse brains, so it is easier to see signs of disease. And because B cells are a sign of long-term disease progression in MS, longer-lived dogs may show signs of human disease better than short-lived mice.
So far, research has shown that dogs are similar to humans in many different ways, including in how they age. Not only have we co-evolved with them and shared an environment but they act the same way during adolescence and old age and their DNA evolves similarly as they get older. Dogs are increasingly seen as good models for human aging also because they suffer from it in many of the same ways humans do and develop similar age-related ailments over time, such as obesity, arthritis, hypothyroidism, and diabetes. They can help researchers understand learn more about how we age and perhaps how to age better. In, 2018 the co-director of the Dog Aging Project, Daniel. E. L. Promislow at the University of Washington, Seattle, laid out the reasons dogs make a good animal in which to study aging and get results that will help people.
Researchers (2020) have already tried to understand the genetics behind ageing in dogs. They sought out patterns of chemical changes in DNA in dogs, a process called methylation that doesn’t alter the content of genes, but does change how active they are. Lab tests can tell how old a human is just from these patterns of methylation. Thanks to this research, the same can be done for dogs. The results will help researchers studying aging in dogs to translate findings to humans. They have already help understand the physical decline seen in aging in dogs and humans, and in fact in all mammals, and shown that it can be linked back to the same genes, regardless of the species. The study of genomics in dogs can help figure out whether there are things in the DNA of dogs that can explain why some of them live a remarkably long time and those findings might be of use in extending healthy aging in people.
Over the past several years, about 30,000 dog owners have entered their pets into the Dog Aging Project, an academic research study backed by $25 million from the National Institutes of Health. The project examines how genetic and environmental factors affect dogs’ aging processes, and it’s also running a trial in which about 200 middle-aged dogs will receive the compound rapamycin, which is used by people to prevent organ transplant rejection and some types of cancer, and seems to delay or reverse aging in tissues. Many companies trying to find ways to prolong life either pharmaceutically or by changing the environment. For example, Cellular Longevity Inc., is developing treatments that extend the life span of dogs while also making them more active in their later years. Canine studies involving caloric restriction have also shown that a dog’s life span can increase by almost two years, while also delaying cancer, degenerative bone disease, and other conditions.
A major appeal of using dogs for these trials is that clinical studies can be conducted in three to five years, with dogs living at home under normal conditions. This is a major step forward from the laboratory mice often used for these types of experiments, which are young and must be bred or altered to have age-related illnesses. The dog-first approach could hence be the key to helping people warm up to anti-aging technology.
In 1880, Louis Pasteur developed an anti-rabies vaccine for dogs, by using dogs in his research.rabies in the dogs. By drying nerve tissue of infected rabbits, Pasteur produced a weakened sample of the virus. When this was given over a 2 week period with stronger doses each time, he was able to immunise the dogs so that they became resistant to the virus.
After his work was published, Pasteur soon found himself being implored by the families of people who had been bitten by rabid dogs. Of the first 350 people he first treated only one went on to develop rabies, compared to the 40-80% that would have developed the fatal condition without his intervention. His vaccine continued to be used until after the Second World War when it was replaced with one produced in cell culture.
Dogs were the first animals to receive an intravenous injection. Sir Christopher Wren, although better known as an architect, developed a system involving a quill and a pig bladder to inject alcohol into a dog’s veins. Over the years this developed into blood transfusions and dogs were test subjects for many of the advances made in the procedure. For more details, visit the blood transfusion page.
Ventricular fibrillation is a common cause of cardiac arrest where the muscles of the heart are uncoordinated and fail to pump blood. This was first described in dogs in the 1840s when scientists discovered it could be induced by ligating the coronary artery or applying an electric current. In 1899, Jean Louis Prevost and Frederic Batelli in Geneva demonstrated that electrical currents could also be used to restore normal rhythm to a dog’s heart, thereby inventing the first electrical defibrillator.
The application of this was aided by the development of the electrocardiogram (ECG) by Willem Einthoven. He won the Nobel Prize in 1924 for this and his characterisation of the changes to the heartbeat with different diseases and stimuli in humans and dogs. In 1947 the surgeon Claude Beck carried out the first successful defibrillation on a human using a machine installed in the operating theatre. However the paddles had to be applied directly to the heart; the first successful "closed chest" defibrillation was performed by Paul Maurice Zoll in 1956. Paul Zoll's achievement was based on research using dogs undertaken a couple of years earlier by William Kouwenhoven and William Milnor, and his own early animal and clinical research on the external pacemaker. In 1962, Bernard Lown refined the wave form of the electric shock to reduce damage to the heart, after he carried out a series of studies involving hundreds of dogs. The Lown waveform became the standard for defibrillation, until it was superseded by the biphasic truncated waveform in the 1990s.
In 1950, WG Bigelow studied the effects of hypothermia on the energy use of dogs. He found that they could be cooled to 20C with no ill effects and their oxygen consumption and heart rate reduced by 85%. This was viewed as a means to allow the heart to be isolated while doing surgery, while minimising the damage to the body. At lower temperatures the heart would undergo ventricular fibrillation and stop completely. Bigelow discovered that the dogs’ heart could be restarted with an electrical charge, leading to the design of the pacemaker.
Further understanding and treatments for the heart raised the possibility of replacing defective heart valves with artificial ones in the 1950s. Initial designs based on the natural structure had issues with strength and clotting when implanted into dogs. Refinements on the design over the next decade eventually led to dogs surviving for over a year without anticoagulant treatment. By October 1961, of the 12 patients who had received artificial mitral valves, two had died from unrelated causes, and three from infections. The remaining patients were well and two had returned to work. Its success encouraged development and testing, in calves and dogs, of further designs, that are still in use today.
The possibility of using transplanted valves was also explored in dogs and the best methods of preparation and storage were established. There was not an adequate supply of human valves so by the mid-1960s it was realised that the answer lay in transplanted valves from other species. Xenograft valves, from pigs, sheep, calves and goats were transplanted into dogs in the early 1970s. Further work to tackle durability and rejection was conducted using rabbits, guinea pigs and rats, resulting in biologically inert, functional and durable valves. Such 'bioprosthetic' valves, usually from pigs, have been used successfully in many human patients.
Treating Anemia (1934)
George Whipple investigated the effects of diet on anaemia by bleeding dogs and comparing their recoveries when fed different diets. He noted that a quick recovery followed a diet consisting of large amounts of liver. He then suggested, and tested, that a liver-rich diet could be used to treat pernicious anaemia in humans. His success in treating pernicious anaemia was recognised by a Nobel Prize in 1934, although we now know that the anaemia in the dogs was treated by the iron in the liver, while the pernicious anaemia in humans was responding to the extra vitamin B12.
Hormonal therapies to treat cancer (1966)
Prostate cancer only naturally occurs in significant numbers in humans and dogs. While the cancer in dogs shares characteristics with humans, there are differences in the likelihood of the cancer metastasizing and the tissue of the prostate. However, by studying the prostate gland in dogs, Charles Huggins discovered that the growth of tumours was dependant on the natural hormones of the body. Reducing male sex hormones or increasing female hormones could treat prostate cancer. Even patients with only a short time to live showed improvement from this new type of treatment, which had fewer side effects than other therapies. For his work and the treatments he helped to develop, Charles Huggins was awarded a Nobel Prize in 1966.
Stem cell therapy to treat Duchenne muscular dystrophy (2006)
Duchenne muscular dystrophy is the most common form muscular dystrophy, affecting 1 in 3500 boys born. The only animal model that reproduces the human pathology and biochemical mechanisms is the Golden Retriever dog. Researchers took stem cells taken from these dogs and corrected the mutated gene before injecting back into the dogs’ muscle tissue. There the stem cells formed muscle fibre and restored some level of function to the muscles.
Cell transplants to treat spinal cord injury (2012)
In November 2012, researchers published the first double-blinded, randomized, controlled study into using cell transplants to treat spinal cord injury. The trial was conducted on pet dogs, mostly dachshunds, which had had spinal injuries through accidental injury. The researchers took a sample of olfactory ensheathing cells (OECs) from the noses of each of the dogs. These cells were known to promote nerve growth, as the nose is the only part of the body where nerve cells continue to grow in adulthood. This study garnered much media attention with videos of the dogs’ remarkable improvement.
Stem cell therapy (2021)
Based on human regenerative therapies, scientists have developed a novel method to induce stem cell generation from the blood samples of dogs. Stem cells have the potential to differentiate and mature into many specialized cell types. By transplanting stem cells and guiding their differentiation into desired cell types, researchers are effectively able to regenerate damaged tissues, thereby reversing the course various complex diseases.
A research team from Japan, led by Associate Professor Shingo Hatoya (2021), has been working on isolating "induced pluripotent stem cells" (iPSCs) from canine blood samples and have successfully established an efficient and easy generation method of canine iPSCs from peripheral blood mononuclear cells. Through this technique, the scientists hope to advance regenerative therapies in veterinary medicine. This would mean that, in the near future, veterinarians might be able to reverse chronic and degenerative conditions in dogs that were previously thought incurable. The authors also believe that additional research into regenerative therapies for canines might have some ripple effects for human medicine. "Dogs share the same environment as humans and spontaneously develop the same diseases, particularly genetic diseases. »
According to the American Veterinary Medical Association, cancers attack dogs at roughly the same rate as humans, and nearly half of dogs over the age of 10 will end up developing cancer. Science has repeatedly shown that dogs develop cancers similar to humans – in appearance, clinical symptoms, histopathology but also in terms of genetics and similar responses and resistance to treatments. These models are often more relevant than lab induced mouse models. Mice are often genetically similar, too small, age too quickly, and cancer - which is often induced or transplanted - develops in a matter of weeks rather than years, in conditions that often demand to repress the immune system. Tumour growth in mice can thus follow a different trajectory than in humans, in a modified microenvironment compared to spontaneous tumours.
Dogs will naturally develop cancers, which often appear with age, in a heterogeneous population. Pet dogs live in the same environment as their owners and are exposed to the same volatile organic and other compounds. Dogs can be impacted by the same multifactorial inputs that can cause cancer in humans, such as diet, second-hand smoke and pesticides. This means that what happens in dogs is much closer to what is observed in human populations. Especially at the molecular level, several types of tumours show similar characteristics between the two species. Likewise, some basic characteristics of their immune system tend to be closely aligned. Because cancer is, in part, a failure of immune surveillance, these similarities are important and particularly crucial for the study of immunotherapies.
As cancers in dogs and humans occur under similar living environmental conditions, researchers can use canine cancers to better understand human tumour progression. Thus, dogs may hold the key to new therapeutic targets and cancer treatments that will benefit pets as much as their owners. Indeed, if a similar cancerous background exists between the two mammals, developing drugs would become that much faster and more efficient. Testing new therapies in canine models before adapting them to human medicine has many benefits, including speeding up testing and approval of therapies.
In the past, drug trials with canine participants have been responsible for medical breakthroughs ranging from photodynamic therapy for lung tumours, HER2/ neu breast cancer vaccine and embolization of prostate cancer. As an example, the life-science startup On Health has launched FidoCure, a novel program that uses genomics and artificial intelligence to bring more personalized precision cancer treatments to dogs – and the research is impacting human oncology as well. Specifically, FidoCure uses gene sequencing to understand the individual mutations of each dog’s tumours and find the right therapy based on the genetic defects. If the mutations are actionable (6 in 10 in dogs compared to 1 in 10 in humans), targeted therapies can be used. All of these findings collected with vet oncologists are funnelled into a proprietary dataset that improves the predictive accuracy of pre-clinical testing for human drug development, while simultaneously providing pets with beneficial cutting-edge therapies to improve their wellness. The outcomes of these treatments are then recorded, analysed, and routed through several databases informing pharmaceutical discovery, drug label extension, and biomarker-driven therapies for hundreds of human cancer types. These finding in turn, improve how millions of patients afflicted with cancer are treated.
For a new drug to reach clinical trials in humans, regulatory bodies usually require toxicity tests in both a rodent and a non-rodent mammal. The rodent will often be a rat and dogs are usually the other mammal. Dogs are used because they are physiologically similar to humans and are readily available. These tests account for about 75% of the dogs currently used in research.
Despite the emotional and ethical issues around the use of dogs in testing, regulations are slow to change because of potential safety implications if a serious adverse effect is missed at this stage. Much research has gone into finding other animals and in vitro alternatives, however these are limited to only certain tests. For example, hERG assays are used to test whether a drug could interfere with the heartbeat and mini-pigs can be used in cases where dogs are not suitable, such as hormone therapies.
During testing, the dogs can be monitored remotely and continuously through implanted transmitters or specially designed jackets. These keep track of blood pressure, heart rate, body temperature and electrocardiogram while the dogs behave normally. The effects of the drug are also examined on dogs under terminal anaesthesia. This gives researchers a clearer picture of the haemodynamics in addition to the telemetry gained.
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Last edited: 13 July 2021 11:09